CN111511738B - Heteroaromatic derivative regulator, preparation method and application thereof - Google Patents

Heteroaromatic derivative regulator, preparation method and application thereof Download PDF

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CN111511738B
CN111511738B CN201980003046.XA CN201980003046A CN111511738B CN 111511738 B CN111511738 B CN 111511738B CN 201980003046 A CN201980003046 A CN 201980003046A CN 111511738 B CN111511738 B CN 111511738B
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heteroaryl
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CN111511738A (en
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曾蜜
高鹏
许�鹏
程宇
李剑
蔡家强
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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Abstract

Relates to a heteroaromatic derivative regulator, a preparation method and application thereof. In particular to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a Janus kinase inhibitor in treating inflammation related diseases and tumor related diseases.

Description

Heteroaromatic derivative regulator, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a JAK inhibitor, and a preparation method and application thereof.
Background
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family contains JAK1, JAK2, JAK3 and TYK2 subfamily members, each subfamily member mediates different types of cytokine signal pathways, JAK1, JAK2 and TYK2 are expressed in each tissue cell of a human body, and JAK3 is mainly expressed in each hematopoietic tissue cell. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cell factor receptor is combined with a ligand thereof, JAKs coupled with the receptor are activated, so that the receptor is phosphorylated, a phosphorylated tyrosine site can be combined with STAT protein containing an SH2 structural domain, STAT is recruited to the receptor and is phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, the activated STAT dimer is transferred to a cell nucleus and activates target gene transcription of the STAT dimer, and thus, multiple functions of growth, activation, differentiation and the like of multiple cells are regulated and controlled.
The JAK/STAT signal pathway mediates the signal transduction of most of intracellular cytokines and plays a key role in biological processes such as immune regulation, immune cell proliferation and the like. The JAK/STAT signal channel has wide functions, participates in a plurality of important biological processes such as proliferation, differentiation, apoptosis, immunoregulation and the like of cells, and is closely related to a plurality of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and the like; meanwhile, the JAK/STAT signal pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera and essential thrombocythemia, and the mutation of JAK molecules can also cause Acute Myelocytic Leukemia (AML), acute Lymphocytic Leukemia (ALL), ductal breast cancer, non-small cell lung cancer (NSCLC) and other neoplastic diseases.
Inflammatory bowel disease is a chronic inflammatory disease of the intestinal tract, including Ulcerative Colitis (UC) and Crohn's Disease (CD). The existing medicines for treating inflammatory bowel diseases mainly comprise aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics and the like. The treatment of UC mainly comprises the regulation of immune response and the inhibition of inflammation. Currently, sulfasalazine is mainly used for treating mild to moderate UC in clinical practice. While the drugs commonly used for the treatment of mild to severe UC include glucocorticoids, they are not considered as long-term treatments because of the greater risk than benefit. The monoclonal antibody has the problems of high cost of medicines, influence on the safety and effectiveness of the medicines due to the generation of the medicine antibody, inconvenience in intravenous administration mode and the like, and the field still has a far-unsatisfied medical requirement. Many patients receiving treatment have not been alleviated, and up to 80% of patients with crohn's disease and 30% of patients with UC eventually require surgical treatment.
Tofacitinib (Xeljanz) is the first oral JAK inhibitor for treating moderate-to-severe active UC adult patients, has obvious inhibitory activity on JAK1, 2 and 3 subtypes, increases the curative effect of the Tofacitinib, and brings more serious side effects. Adverse reactions include infection, tuberculosis, tumors, anemia, liver damage, increased cholesterol, and the like. The specification for Tofacitinib is indicated by a number of black boxes: severe infections (tuberculosis, bacteria, fungi, viruses) and malignancies (lymphomas, etc.). Due to the wide range of functions mediated by each JAK, these side effects are caused by the simultaneous inhibition of multiple JAKs by the drug. Since JAKs are widely involved in the regulation of immune cells, JAK inhibitors inevitably cause side effects associated with immunosuppression, such as severe infection, even tumorigenesis, and the like. Even with the numerous highly selective inhibitors currently under investigation, such side effects caused by the inhibitory target are unavoidable.
In view of the good curative effect and the serious side effect related to various targets of the JAK inhibitor, the problem to be solved urgently at present is to develop a JAK inhibitor medicament with higher safety. Since inflammatory bowel disease occurs on the luminal surface of the gastrointestinal tract and acts without the need for drugs to enter the blood system, the development of a drug that reduces systemic exposure of the drug in the blood circulation and increases the local exposure of the drug at the site of inflammation is a good strategy to increase safety. International application WO2016191524A1 reports that Theravance synthesizes a series of compounds that have very low systemic exposure and form an enrichment at the site of intestinal inflammation, and that are effective in treating intestinal inflammation without causing serious side effects, indicating that the strategy has great feasibility and may generate significant clinical application value.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defect that the side effect is serious while the existing JAK inhibitor plays a therapeutic role, and provides a heteroaromatic derivative regulator, a preparation method and application thereof. The heteroaromatic derivative has a good inhibition effect on JAK kinase, can obviously improve the local exposure at a treatment part, and has good targeting property.
The present invention solves the above-mentioned problems by the following means.
A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000021
wherein:
L 1 selected from the group consisting of a bond, alkylene, alkylideneAlkenyl, alkynyl, cycloalkyl, heterocyclyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -, or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of bonds, oxygen atoms, sulfur atoms, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -, or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -, or-C (O) NR aa -；
Ring A is a 6-14 membered heteroaryl, wherein said 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; preferably a 5 and 5 membered fused heteroaryl group, a 5 and 6 membered fused heteroaryl group or a 6 and 6 membered fused heteroaryl group;
ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group, 6-14 membered fused heterocyclic group or 6-14 membered spiro heterocyclic group;
ring C is heteroaryl;
R 1 selected from the group consisting of hydrogen atom, deuterium atom, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 2 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 3 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl groupCyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 4 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group;
R aa 、R bb 、R cc And R dd The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl groups;
x is an integer of 0, 1, 2 or 3;
y is an integer of 0, 1, 2, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 1 selected from the group consisting of a bond, alkylene, cycloalkyl, heterocyclyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -, or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of a bond, an oxygen atom, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -, or- (CH) 2 ) n1 S(O) m1 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 selected from the group consisting of a bond, -NR aa -, or-C (O) NR aa -；
Ring A is a 6-14 membered fused heteroaryl;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, 6-14 membered fused heterocyclic group or 6-14 membered spiro heterocyclic group;
ring C is heteroaryl;
R 1 selected from hydrogen, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein said alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, cyano, alkyl or alkoxy;
R 2 selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, amino, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 C(O)R cc 、-(CH 2 ) n1 SR aa Or is- (CH) 2 ) n1 NR aa R bb (ii) a Wherein said alkyl, alkoxy, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted or unsubstituted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted alkoxy, unsubstituted cycloalkyl, substituted or unsubstituted amino, Substituted or unsubstituted heterocyclic group, or unsubstituted heteroaryl group; wherein "substituted" means substituted with alkyl, or halogen;
R cc is a heterocyclic group; said heterocyclyl is optionally substituted with unsubstituted alkyl;
R 3 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, halogens, hydroxyl groups, cyano groups, cycloalkyl groups, heterocyclic groups, - (CH) 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 S(O) m1 R aa Or is- (CH) 2 ) n1 S(O) m1 NR aa R bb (ii) a Wherein said alkyl, alkoxy, cycloalkyl, or heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, unsubstituted alkyl, or unsubstituted alkoxy;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an amino group, or a heteroaryl group; wherein said alkyl and amino groups are optionally further substituted with one or more substituents selected from the group consisting of unsubstituted alkyl, substituted or unsubstituted heterocyclyl and unsubstituted heteroaryl; wherein "substituted" means substituted with alkyl, or halogen;
x is 0, 1, 2 or 3;
y is 0, 1, 2 or 3;
m 1 is 0, 1 or 2;
m 2 is 0, 1 or 2; and is provided with
n 1 Is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above):
L 1 Selected from the group consisting of a bond, alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Selected from a bond, an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NR aa -；
Ring A is a 6-14 membered fused heteroaryl;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 selected from a hydrogen atom, an alkyl group, a haloalkyl group, an amino group, a heterocyclic group, or a heteroaryl group; wherein said alkyl, amino, heterocyclyl, or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, alkyl, or alkoxy;
R 2 selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group; wherein said heteroaryl is optionally further substituted with one or more substituents selected from unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl;
R 3 selected from hydrogen atoms, alkyl groups, hydroxyalkyl groups, halogens, cyano groups, cycloalkyl groups, - (CH) 2 ) n1 C(O)R aa Or is- (CH) 2 ) n1 C(O)NR aa R bb (ii) a Wherein said alkyl is optionally further substituted with a substituent selected from the group consisting of hydroxy;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, an alkyl group, or an amino group;
x is 0, 1, 2 or 3;
y is 0, 1, 2 or 3;
m 1 is 0, 1 or 2;
m 2 is 0, 1 or 2; and is provided with
n 1 Is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): l is 1 Selected from the group consisting of a bond, aAlkyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is a radical of an alcohol 2 Selected from a bond, an oxygen atom, or-NR 4 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): r is 4 Selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): l is a radical of an alcohol 3 is-NR aa -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): ring A is a 6-14 membered fused heteroaryl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): ring C is heteroaryl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): r 1 Selected from a hydrogen atom, an alkyl group, a haloalkyl group, an amino group, a heterocyclic group, or a heteroaryl group; wherein said alkyl, amino, heterocyclyl, or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, alkyl, or alkoxy.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): r 2 Selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group; wherein said heteroaryl is optionally further substituted with one or more substituents selected from unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): r is 3 Selected from hydrogen, alkyl, hydroxyalkyl, halogen, cyano, cycloalkyl, - (CH) 2 ) n1 C(O)R aa Or is- (CH) 2 ) n1 C(O)NR aa R bb (ii) a Wherein said alkyl is optionally further substituted with hydroxyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): r aa And R bb Are the same or different and are each independently selected from a hydrogen atom, an alkyl group, or an amino group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): x is 0, 1, 2 or 3.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): y is 0, 1, 2 or 3.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): m is 1 Is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): m is 2 Is 0, 1 or 2.
In some aspects of the inventionIn the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as defined above): n is 1 Is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 1 When it is an alkylene group, said alkylene group is preferably C 1 -C 4 Alkylene of, e.g. -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, more preferably-CH 2 -, or- (CH) 2 ) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 1 When cycloalkyl is used, the cycloalkyl is preferably C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000081
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 1 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000082
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 When said- (CH) 2 ) n1 C(O)(CH 2 ) m1 -preferably-C (O) -, -C (O) CH 2 -, or-CH 2 C(O)-。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 When is- (CH) of 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -preferably-C (O) CH 2 NH-、-C(O)CH 2 N(CH 3 )-、-C(O)CH 2 NHCH 2 -、-C(O)CH 2 NH(CH 2 ) 2 -, or-CH 2 C(O)N(CH 3 )-。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 1 is-NR aa (CH 2 ) n1 When said is-NR aa (CH 2 ) n1 -preferably-NH (CH) 2 ) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 1 Is- (CH) 2 ) n1 S(O) m1 When said- (CH) 2 ) n1 S(O) m1 -preferably-S (O) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 1 Is- (CH) 2 ) n1 S(O) m1 NR aa When is- (CH) of 2 ) n1 S(O) m1 NR aa -preferably-S (O) 2 NH-。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is a radical of an alcohol 1 Is connected to ring B, L 1 Is at the right endAnd R 1 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 2 is-CR aa R bb When said-CR is aa R bb -preferably-CH 2 -or-CH (OH) -.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 2 Is- (CH) 2 ) n1 C (O) -, said- (CH) 2 ) n1 C (O) -, preferably-C (O) -.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 2 is-NR 4 When said-NR is 4 -preferably-NH-or-N (CH) 3 )-。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 2 Is- (CH) 2 ) n1 S(O) m1 When said- (CH) 2 ) n1 S(O) m1 -preferably-S (O) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is 2 Is connected to ring A, L 2 Is connected to ring B.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 4 When alkyl, the alkyl is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said L is 3 is-NR aa When said-NR is aa -NH-is preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said L is 3 is-C (O) NR aa When said is-C (O) NR aa -preferably-C (O) NH-.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): l is 3 Is connected to ring C, L 3 Is connected to ring B.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when the ring A is a 6-14-membered thick heteroaryl group, the 6-14-membered thick heteroaryl group is preferably a 5-and 6-membered thick heteroaryl group in which "hetero atom (S) are selected from one or more of N, O and S and the number of hetero atoms is 1-4", more preferably a 6-and 6-membered thick heteroaryl group in which "hetero atom (S) are selected from one or more of N, O and S and the number of hetero atoms is 1-4", or a 6-and 6-membered thick heteroaryl group in which "hetero atom (S) are selected from one or more of N, O and S and the number of hetero atoms is 1-4". The 5-and 6-membered thick heteroaryl group is preferably thienopyrimidinyl or pyrazolopyrimidyl, benzopyrolyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, imidazopyridazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, triazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, triazolopyrazinyl, pyrrolotriazinyl, imidazotriazinyl, or imidazopyrazinone, more preferably thienopyrimidinyl, pyrrolotriazinyl, and imidazopyrazinone
Figure BDA0002321528230000101
Figure BDA0002321528230000102
Figure BDA0002321528230000111
Further preferred is
Figure BDA0002321528230000112
Figure BDA0002321528230000113
The 6-and 6-membered thick heteroaryl group is preferably an isoquinolinyl group, a naphthyridinyl group, a pyridopyrazinyl group, a pyridopyrimidinyl group, a quinazolinyl group, a pteridinyl group, a quinoxalinyl group, a dihydropyranopyrimidinyl group, a dihydrodioxadienopyrimidinyl group, a,
Figure BDA0002321528230000114
More preferably
Figure BDA0002321528230000115
Figure BDA0002321528230000116
Figure BDA0002321528230000117
Further preferred is
Figure BDA0002321528230000118
Figure BDA0002321528230000119
Left end of ring A and L 3 Connected, the right end of ring A with L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when the ring B is a 3-to 10-membered heteromonocyclic group, the 3-to 10-membered heteromonocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atomsHeterocyclic radicals, e.g.
Figure BDA0002321528230000121
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when ring B is a 6-14-membered bridged heterocyclic group, the 6-14-membered bridged heterocyclic group is preferably a 6-14-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000122
Also for example
Figure BDA0002321528230000123
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when the ring B is a 6-14-membered fused heterocyclic group, the 6-14-membered fused heterocyclic group is preferably a 6-14-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000124
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when the ring B is a 6-14-membered spiroheterocyclic group, the 6-14-membered spiroheterocyclic group is preferably a 6-14-membered spiroheterocyclic group having "one or more hetero atoms selected from N, O and S and 1-4 hetero atoms", more preferably a 7-10-membered spiroheterocyclic group having "one or more hetero atoms selected from N, O and S and 1-3 hetero atoms", for example
Figure BDA0002321528230000125
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): upper end of ring B and L 1 Connected, the lower end of ring B with L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when the ring C is a heteroaryl group, the heteroaryl group is preferably a 6-to 14-membered heteroaryl group having one or more heteroatoms selected from N, O and S and 1 to 4, more preferably a 5-to 6-membered monoheteroaryl group having one or more heteroatoms selected from N, O and S and 1 to 3, or an 8-to 10-membered fused heteroaryl group having one or more heteroatoms selected from N, O and S and 1 to 3. Said 5-to 6-membered monoheteroaryl is preferably pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrimidinyl or pyrazinyl, e.g.
Figure BDA0002321528230000131
Also for example
Figure BDA0002321528230000132
Figure BDA0002321528230000133
Said 8-to 10-membered fused heteroaryl group is preferably indazolyl, or pyrazolopyridyl, e.g.
Figure BDA0002321528230000134
Figure BDA0002321528230000135
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 1 When alkyl, the alkyl is preferably C 1 -C 8 Alkyl of (2), furtherPreferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 When it is a haloalkyl group, said haloalkyl group is preferably C 1 -C 8 Haloalkyl of, more preferably C 1 -C 6 Halogenoalkyl of (2), further preferably C 1 -C 3 Haloalkyl of, e.g., -CHF 2 Or CF 3 。
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 1 When it is an alkoxy group, the alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group or an ethoxy group is further preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 When halogen is used, fluorine is preferred as the halogen.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 When cycloalkyl is used, the cycloalkyl is preferably C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000141
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when saidR of (A) to (B) 1 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000142
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 When aryl, the aryl group is preferably a 6-to 10-membered aryl group, more preferably a phenyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 In the case of the heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000143
Figure BDA0002321528230000144
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 1 Is alkyl, amino, heterocyclyl, aryl or heteroaryl, said alkyl, amino, heterocyclyl, aryl or heteroaryl being optionally further substituted by halogen, said halogen being preferably fluorine.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 1 Is amino, heterocyclyl, aryl or heteroaryl, saidWhen the amino, heterocyclic, aryl or heteroaryl group of (a) is optionally further substituted by an alkyl group, said alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 1 Is alkyl, amino, heterocyclyl, aryl or heteroaryl, said alkyl, amino, heterocyclyl, aryl or heteroaryl being optionally further substituted by alkoxy, said alkoxy preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 2 When alkyl, the alkyl is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When it is an alkoxy group, the alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group or an ethoxy group is further preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as defined in the specification)As indicated previously): when said R is 2 When halogen is used, the halogen is preferably fluorine, chlorine or bromine.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When cycloalkyl is used, the cycloalkyl is preferably C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000151
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 2 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000152
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When aryl, the aryl group is preferably a 6-to 10-membered aryl group, more preferably a phenyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 2 In the case of the heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000153
Figure BDA0002321528230000161
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is- (CH) 2 ) n1 C(O)R cc When is in the range of- (CH) 2 ) n1 C(O)R cc Preference is given to
Figure BDA0002321528230000162
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is- (CH) 2 ) n1 SR aa When said- (CH) 2 ) n1 SR aa Preference is given to
Figure BDA0002321528230000163
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is- (CH) 2 ) n1 NR aa R bb When is in the range of- (CH) 2 ) n1 NR aa R bb Preference is given to
Figure BDA0002321528230000164
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is an alkyl group, said alkyl group being optionally further substituted by an unsubstituted alkoxy group, said alkoxy group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 Alkoxy, e.g. methoxy, ethoxy, propoxy or isopropoxy, furtherMethoxy is preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When the alkyl group is an alkyl group, said alkyl group being optionally further substituted with a substituted or unsubstituted heterocyclic group, said heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000165
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When the alkyl group is optionally further substituted with a substituted or unsubstituted heterocyclic group, the heterocyclic group is preferably substituted with an alkyl group, preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 2 Is an alkoxy group, said alkoxy group being optionally further substituted with an unsubstituted alkoxy group, said unsubstituted alkoxy group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is alkoxyWhen the alkoxy group is optionally further substituted with a substituted or unsubstituted heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000171
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When the alkoxy group is optionally further substituted by a substituted or unsubstituted heterocyclic group, the heterocyclic group is preferably substituted by an alkyl group, preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 2 When the alkoxy group is optionally further substituted with an unsubstituted heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000172
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is an amino group, said amino group being optionally further substituted with an unsubstituted alkyl group, said alkyl group preferably being C 1 -C 8 Alkyl of (2), more preferablyC 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted with an unsubstituted alkyl group, said alkyl group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted by an unsubstituted alkoxy group, said alkoxy group preferably being C 1 -C 8 Alkoxy of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted with a substituted or unsubstituted amino group, said amino group being preferably substituted with an alkyl group, said alkyl group being preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is heteroaryl, said heteroaryl beingWhen further substituted by a substituted or unsubstituted alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 When the heteroaryl group is optionally further substituted with a substituted or unsubstituted alkyl group, the alkyl group is preferably substituted with a halogen, preferably fluorine.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is heteroaryl, said heteroaryl being optionally further substituted with unsubstituted alkoxy, said alkoxy preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 2 Is heteroaryl, said heteroaryl being optionally further substituted by unsubstituted cycloalkyl, preferably said cycloalkyl is C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000181
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is cc When it is a heterocyclic group, said heterocyclic group is preferably a "hetero atom selected from one or more of N, O and SPlural kinds of 3-to 8-membered heteromonocyclic group having 1 to 4 "hetero atoms, more preferably" hetero atom is one or more selected from N, O and S, and 1 to 3 "hetero atom is 4-to 6-membered heteromonocyclic group, for example
Figure BDA0002321528230000182
Figure BDA0002321528230000183
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is cc Is a heterocyclic group, and when said heterocyclic group is optionally substituted with an unsubstituted alkyl group, said alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 3 When alkyl, the alkyl is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 3 In the case of hydroxyalkyl, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Hydroxyalkyl of (2), further preferably C 1 -C 3 The hydroxyalkyl group of (2) is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxyisopropyl group, and a hydroxymethyl group is further preferred.
In some technical schemes of the invention, in the compound shown in the general formula (I), certain groups are fixed The definitions are as follows (undefined groups are as indicated above): when said R is 3 When it is a haloalkyl group, said haloalkyl group is preferably C 1 -C 8 Haloalkyl of, more preferably C 1 -C 6 Halogenoalkyl of (2), further preferably C 1 -C 3 Haloalkyl of, e.g., -CHF 2 Or CF 3 。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 When it is an alkoxy group, said alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 When halogen is used, fluorine is preferred as the halogen.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 When cycloalkyl is used, the cycloalkyl is preferably C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000191
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000192
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is alkyl, said alkyl being optionally further substituted by halogen, said halogen being preferably fluorine.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 3 Is an alkyl group, said alkyl group being optionally further substituted by an unsubstituted alkoxy group, said alkoxy group preferably being C 1 -C 8 Alkoxy of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is an alkoxy group, said alkoxy group being optionally further substituted with an unsubstituted alkyl group, said alkyl group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 In the case of cycloalkyl, said cycloalkyl is preferably substituted by hydroxy.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is a heterocyclic group, said heterocyclic group being optionally further substituted with an unsubstituted alkyl group, said alkyl group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is alkyl, when said alkyl is substituted by halogen, said R 3 is-CHF 2 Or CF 3 。
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is an alkyl group, when said alkyl group is substituted with a hydroxyl group, said R 3 Is composed of
Figure BDA0002321528230000201
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is an alkyl group, when said alkyl group is substituted with an unsubstituted alkoxy group, said R 3 Is composed of
Figure BDA0002321528230000202
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is cycloalkyl, said cycloalkyl being optionally further substituted by hydroxy, said R 3 Is composed of
Figure BDA0002321528230000203
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is a heterocyclic group, said heterocyclic group being optionally substitutedWhen one step is substituted by unsubstituted alkyl, R is 3 Is composed of
Figure BDA0002321528230000211
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 3 Is- (CH) 2 ) n1 C(O)R aa When is in the range of- (CH) 2 ) n1 C(O)R aa Preference is given to
Figure BDA0002321528230000212
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is 3 Is- (CH) 2 ) n1 C(O)NR aa R bb When is in the range of- (CH) 2 ) n1 C(O)NR aa R bb Preference is given to
Figure BDA0002321528230000213
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is- (CH) 2 ) n1 S(O) m1 R aa When said- (CH) 2 ) n1 S(O) m1 R aa Preference is given to
Figure BDA0002321528230000214
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is 3 Is- (CH) 2 ) n1 S(O) m1 NR aa R bb When said- (CH) 2 ) n1 S(O) m1 NR aa R bb Preference is given to
Figure BDA0002321528230000215
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb When independently an alkyl group, said alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb When independently a heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000216
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb Independently an alkyl group, said alkyl group being optionally further substituted with a substituted or unsubstituted heterocyclic group, said heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S, and a hetero atom number of 1 to 4", more preferably a 4-to 6-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S, and a hetero atom number of 1 to 3", for example
Figure BDA0002321528230000221
Figure BDA0002321528230000222
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb Independently an alkyl group, which alkyl group is optionally further substituted by a substituted or unsubstituted heterocyclyl group, said heterocyclyl group is preferably substituted by an alkyl group, preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb Independently an alkyl group, said heteroaryl group being preferably a 5-to 10-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, with 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, with 1 to 3 heteroatoms", for example
Figure BDA0002321528230000223
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): when said R is aa And R bb Independently an amino group, which is optionally further unsubstituted alkyl, said alkyl group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): -L 1 -a preferred bond, -CH 2 -、-(CH 2 ) 2 -、
Figure BDA0002321528230000224
-C(O)-、-C(O)CH 2 -、-CH 2 C(O)-、-C(O)CH 2 NH-、-C(O)CH 2 N(CH 3 )-、-C(O)CH 2 NHCH 2 -、-C(O)CH 2 NH(CH 2 ) 2 -、-CH 2 C(O)N(CH 3 )-、-NH(CH 2 ) 2 -、-S(O) 2 -, or-S (O) 2 NH-, more preferably a bond, -CH 2 -、-(CH 2 ) 2 -、-C(O)-、-C(O)CH 2 -、-C(O)CH 2 NH-、-C(O)CH 2 N(CH 3 )-、-C(O)CH 2 NH(CH 2 ) 2 -、-CH 2 C(O)N(CH 3 ) -, or-S (O) 2 -；L 1 Is connected to ring B, L 1 Right end of (1) and R 1 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): said L 2 Preferably a bond, an oxygen atom, -CH 2 -、-CH(OH)-、-C(O)-、-NH-、-N(CH 3 ) -or-S (O) 2 -, more preferably a bond, an oxygen atom, -NH-, or-N (CH) 3 )-；L 2 Is connected to ring A, L 2 Is connected to ring B.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): said L 3 Preferably a bond, -NH-or-C (O) NH-, more preferably-NH-; l is a radical of an alcohol 3 Is connected to ring C, L 3 Is connected to ring B.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): the ring A is preferably a group selected from,
Figure BDA0002321528230000231
Figure BDA0002321528230000241
Figure BDA0002321528230000242
More preferably
Figure BDA0002321528230000243
Figure BDA0002321528230000244
Figure BDA0002321528230000245
Left end of ring A and L 3 Connected with the right end of the ring A and L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): the ring B is preferably a group selected from,
Figure BDA0002321528230000246
Figure BDA0002321528230000247
more preferably
Figure BDA0002321528230000248
Figure BDA0002321528230000249
Upper end of ring B and L 1 Connected, the lower end of ring B with L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): the ring C is preferably a group selected from,
Figure BDA0002321528230000251
Figure BDA0002321528230000252
more preferably
Figure BDA0002321528230000253
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): said R 1 Preferably hydrogen atom, methyl group, ethyl group, fluorine group, methoxy group, ethoxy group, phenyl group, cyano group, -CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 F、-NHCH 2 CH 2 CN、
Figure BDA0002321528230000254
Figure BDA0002321528230000255
Figure BDA0002321528230000256
More preferably a hydrogen atom, methyl group, ethyl group, fluorine group, cyano group, -CHF 2 、-CH 2 CH 2 CN、-CH 2 CH 2 F、
Figure BDA0002321528230000257
Figure BDA0002321528230000258
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): said R 2 Preferably hydrogen atom, fluorine, chlorine, bromine, amino group, hydroxyl group, cyano group, methyl group, methoxy group,
Figure BDA0002321528230000259
Figure BDA00023215282300002510
Figure BDA0002321528230000261
Figure BDA0002321528230000262
More preferably a hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy group,
Figure BDA0002321528230000263
Figure BDA0002321528230000264
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): r is as described 3 Preferably a hydrogen atom, methyl, ethyl, fluorine, cyano, -CHF 2 、CF 3 、
Figure BDA0002321528230000265
Figure BDA0002321528230000266
More preferably a hydrogen atom, methyl group, ethyl group, fluorine group, cyano group,
Figure BDA0002321528230000267
Figure BDA0002321528230000268
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): structure-L 1 -R 1 Preference is given to
Figure BDA0002321528230000269
Figure BDA00023215282300002610
Figure BDA0002321528230000271
More preferably
Figure BDA0002321528230000272
Figure BDA0002321528230000273
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 1 and R 1 Is defined as any one of the following groups:
(1)L 1 is alkylene, R 1 Is cycloalkyl, heterocyclyl or 5-membered heteroaryl; wherein said cycloalkyl or heterocyclyl is optionally further substituted by cyano; said 5-membered heteroaryl is optionally further substituted with alkyl;
(2)L 1 is cycloalkyl or heterocyclyl, R 1 Is cyano or alkyl; said alkyl is optionally further substituted with cyano;
(3)L 1 is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is heterocyclyl or 5-membered heteroaryl; said heterocyclyl or 5-membered heteroaryl is optionally further substituted with alkyl;
(4)L 1 is-C (O) (CH) 2 ) m1 NH(CH 2 ) m2 -，R 1 Is hydrogen atom, alkoxy, cycloalkyl, aryl or heteroaryl; said aryl group is optionally further substituted with an alkoxy group;
(5)L 1 is- (CH) 2 ) n1 S(O) m1 -，R 1 Is a 5 membered heteroaryl; said 5-membered heteroaryl is optionally further substituted with alkyl;
(6)L 1 is- (CH) 2 ) n1 S(O) m1 NH-，R 1 Is an alkyl group; said alkyl is optionally further substituted with cyano.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 1 and R 1 Is defined by any one of the following groups:
(1)L 1 is alkylene, R 1 Is cycloalkyl, heterocyclyl, or 5-membered heteroaryl; wherein said cycloalkyl or heterocyclyl is optionally further substituted by cyano; said 5-membered heteroaryl is optionally further substituted with alkyl;
(2)L 1 is cycloalkyl, or heterocyclyl, R 1 Is cyano, or alkyl; said alkyl is optionally further substituted with cyano;
(3)L 1 is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is heterocyclyl, or 5-membered heteroaryl; said heterocyclyl, or 5-membered heteroaryl, is optionally further substituted with alkyl;
(4)L 1 is-C (O) (CH) 2 ) m1 NH(CH 2 ) m2 -，R 1 Is a hydrogen atom, alkoxy group, cycloalkyl group, aryl group, or heteroaryl group; said aryl group is optionally further substituted with an alkoxy group;
(5)L 1 is- (CH) 2 ) n1 S(O) m1 -，R 1 Is a 5 membered heteroaryl; said 5-membered heteroaryl is optionally further substituted with alkyl;
(6)L 1 is- (CH) 2 ) n1 S(O) m1 NH-，R 1 Is an alkyl group; said alkyl is optionally further substituted with cyano;
L 2 is-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring A is a 6-14 membered fused heteroaryl;
ring B is selected from 3-10 membered heterocyclyl, or 6-14 membered bridged heterocyclyl;
ring C is heteroaryl;
R 2 selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 1 and R 1 Is defined as any one of the following groups:
(1)L 1 is alkylene, R 1 Is a 5 membered heteroaryl; wherein said 5-membered heteroaryl is optionally further substituted with alkyl;
(2)L 1 is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is heterocyclyl or 5-membered heteroaryl; said heterocyclyl or 5-membered heteroaryl is optionally further substituted with alkyl;
(3)L 1 is-C (O) (CH) 2 ) m1 NH(CH 2 ) m2 -，R 1 Is a hydrogen atom;
(4)L 1 is- (CH) 2 ) n1 S(O) m1 -，R 1 Is a 5 membered heteroaryl; said 5-membered heteroaryl is optionally further substituted with alkyl;
L 2 is-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring A is a 6-14 membered fused heteroaryl;
ring B is a 6-14 membered bridged heterocyclic group;
ring C is heteroaryl;
R 2 selected from a hydrogen atom, or an alkyl group;
R 3 Selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): l is 1 Is alkylene, R 1 Is cycloalkyl, heterocyclyl or 5-membered heteroaryl; wherein said cycloalkyl or heterocyclyl is optionally further substituted by cyano; said 5-membered heteroaryl is optionally further substituted with alkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as defined above)Shown below): l is 1 Is cycloalkyl or heterocyclyl, R 1 Is cyano or alkyl; said alkyl group is optionally further substituted with cyano.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is heterocyclyl or 5-membered heteroaryl; said heterocyclyl or 5-membered heteroaryl is optionally further substituted with alkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is 1 is-C (O) (CH) 2 ) m1 NH(CH 2 ) m2 -，R 1 Is hydrogen atom, alkoxy, cycloalkyl, aryl or heteroaryl; said aryl group is optionally further substituted with an alkoxy group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is a radical of an alcohol 1 Is- (CH) 2 ) n1 S(O) m1 -，R 1 Is a 5 membered heteroaryl; said 5-membered heteroaryl is optionally further substituted with alkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): l is a radical of an alcohol 1 Is- (CH) 2 ) n1 S(O) m1 NH-，R 1 Is an alkyl group; said alkyl group is optionally further substituted with cyano.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000291
Figure BDA0002321528230000301
Figure BDA0002321528230000311
in some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
ring B is selected from
Figure BDA0002321528230000312
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above):
ring B is selected from
Figure BDA0002321528230000313
L 1 Is alkylene or-NH (CH) 2 ) n1 -；
L 2 Selected from a bond, or-NH-;
L 3 Is NH;
ring A is a 6-14 membered fused heteroaryl;
ring C is heteroaryl;
R 1 is cyano;
R 2 is a hydrogen atom;
R 3 selected from a hydrogen atom, or an alkyl group;
n 1 is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
ring B is
Figure BDA0002321528230000321
L 1 Is an alkylene group;
L 2 is a bond;
L 3 is NH;
ring A is a 6-14 membered fused heteroaryl;
ring C is heteroaryl;
R 1 is a cyano group;
R 2 is a hydrogen atom;
R 3 is a hydrogen atom or an alkyl group.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000322
Figure BDA0002321528230000331
in some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 2 selected from the group consisting of a bond, -CHR aa -、-(CH 2 ) n1 C (O) -, or- (CH) 2 ) n1 S(O) 2 -；R aa Selected from a hydrogen atom, or a hydroxyl group;
n 1 is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 2 selected from the group consisting of a bond, -CHR aa -、-(CH 2 ) n1 C (O) -or- (CH) 2 ) n1 S(O) 2 -；R aa Selected from a hydrogen atom or a hydroxyl group;
n 1 is 0, 1 or 2;
L 1 is an alkylene group;
L 3 is NH;
ring A is a 6-14 membered fused heteroaryl;
Ring B is a 6-14 membered bridged heterocyclic group;
ring C is heteroaryl;
R 1 is a cyano group;
R 2 selecting a hydrogen atom, an alkyl group, an alkoxy group, or a heterocyclic group;
R 3 selected from a hydrogen atom, or an alkyl group.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000341
in some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
ring A is a 6-14 membered fused heteroaryl group and ring A is not
Figure BDA0002321528230000342
Figure BDA0002321528230000343
Wherein, the left end of the ring A and the L 3 Connected with the right end of the ring A and L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
ring A is a 6-14 membered fused heteroaryl group and ring A is not
Figure BDA0002321528230000351
Figure BDA0002321528230000352
Wherein, the left end of the ring A and the L 3 Connected, the right end of ring A with L 2 Connecting;
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Selected from a bond, an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 selected from a hydrogen atom, an alkyl group, an alkoxy group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; said heterocyclyl or heteroaryl being optionally further substituted by cyano or alkyl; said aryl group is optionally further substituted with an alkoxy group;
R 2 Selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, or a heterocyclic group; said alkyl group being optionally further substituted with an unsubstituted alkoxy group, an alkyl substituted or unsubstituted heterocyclyl group; said heterocyclyl is optionally further substituted with alkyl;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
R aa selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above):
ring A is a 6-14 membered fused heteroaryl group and ring A is not
Figure BDA0002321528230000353
Figure BDA0002321528230000354
Wherein, the left end of the ring A and the L 3 Connected, the right end of ring A with L 2 Connecting;
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Selected from an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 selected from a hydrogen atom, an alkyl group, an alkoxy group, a cyano group, a heterocyclic group, or a heteroaryl group; said heterocyclyl or heteroaryl being optionally further substituted by cyano or alkyl;
R 2 selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, or a heterocyclic group; said alkyl is optionally further substituted with a substituted alkoxy, alkyl substituted or unsubstituted heterocyclyl; said heterocyclyl is optionally further substituted with alkyl;
R 3 Selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
R aa selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): when the ring A is a 6-14 membered thick heteroaryl group, the 6-14 membered thick heteroaryl group is preferably a 5 and 6 membered thick heteroaryl group in which "hetero atom number is 1-4" 6-14 membered thick heteroaryl group, more preferably a 6 and 6 membered thick heteroaryl group in which "hetero atom number is 1-4" and "hetero atom number is one or more N, O and S". Said 5-and 6-membered thick heteroaryl group is preferably thienopyrimidinyl or pyrazolopyrimidyl, benzopyrolyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, imidazopyridazinyl, pyrrolopyrimidinyl, pyrazolopyrimidyl, imidazopyrimidinyl, triazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidylPyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, triazolopyrazinyl, pyrrolotriazinyl, imidazotriazinyl or imidazopyrazinone group, more preferably
Figure BDA0002321528230000361
Figure BDA0002321528230000362
Figure BDA0002321528230000371
Figure BDA0002321528230000372
The 6-and 6-membered thick heteroaryl group is preferably an isoquinolinyl group, a naphthyridinyl group, a pyridopyrazinyl group, a pyridopyrimidinyl group, a quinazolinyl group, a pteridinyl group, a quinoxalinyl group, a dihydropyranopyrimidinyl group, a dihydrodioxadienopyrimidinyl group, a,
Figure BDA0002321528230000373
More preferably
Figure BDA0002321528230000374
Figure BDA0002321528230000381
Figure BDA0002321528230000382
Wherein, the left end of the ring A and the L 3 Connected, the right end of ring A with L 2 Are connected.
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): said ring A is preferably pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, triazolopyrazinyl,
Figure BDA0002321528230000383
Pyridopyrazinyl, pteridinyl or quinoxalyl, more preferably
Figure BDA0002321528230000384
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): said ring A is preferably pyrazolopyrimidinyl or pyrazolopyrazinyl, more preferably pyrazolopyrimidinyl
Figure BDA0002321528230000385
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): the ring A is preferably imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl or imidazotriazinyl, more preferably imidazopyridazinyl
Figure BDA0002321528230000391
Figure BDA0002321528230000392
In some embodiments of the present invention, in the compounds represented by the general formula (I), certain groups are defined as follows (undefined groups are as shown above): said ring A is preferably thiazolopyrimidinyl, more preferably
Figure BDA0002321528230000393
Figure BDA0002321528230000394
In some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above): the ring A is preferably a triazolopyridyl group, a triazolopyrimidinyl group or a triazolopyrazinyl group, more preferably a triazolopyridyl group
Figure BDA0002321528230000395
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000401
Figure BDA0002321528230000411
Figure BDA0002321528230000421
Figure BDA0002321528230000431
Figure BDA0002321528230000441
in some technical schemes of the invention, the compound shown in the formula (I) is preferably a compound shown in a formula (I-1),
Figure BDA0002321528230000442
wherein ring D is heterocycloalkenyl, aryl, or heteroaryl;
X 1 、X 2 and X 3 Independently CH or N;
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; saidHeterocyclyl is optionally further substituted by cyano; said heteroaryl is optionally further substituted with alkyl;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted with alkyl;
L 2 、L 3 、R 2 、R 3 ring B, ring C, x and y are as previously defined.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above):
ring D is heterocycloalkenyl, aryl, or heteroaryl;
X 1 、X 2 and X 3 Independently CH or N;
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano; said heteroaryl is optionally further substituted with alkyl;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted with alkyl;
L 2 selected from an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered monocyclic heterocyclic group, 6-14 membered fused heterocyclic group, or 6-14 membered bridged heterocyclic group;
Ring C is heteroaryl;
R 2 selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 OR cc Or is- (CH) 2 ) n1 NR aa R bb (ii) a Said alkyl is optionally further substituted with an alkyl substituted or unsubstituted heterocyclyl; said alkoxy group is optionally further substituted with an unsubstituted alkoxy group, an alkyl substituted or unsubstituted heterocyclic group, or an unsubstituted heteroaryl group; said heterocyclyl is optionally further substituted with an amino group selected from unsubstituted alkyl, unsubstituted alkoxy, or alkyl; said heteroaryl is optionally further substituted with a group selected from halogen substituted or unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, or an alkyl group; said alkyl is optionally further substituted with a heterocyclic group selected from alkyl substituted or unsubstituted, or unsubstituted heteroaryl;
R cc is a heterocyclic group; said heterocyclyl is optionally further substituted with unsubstituted alkyl;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above):
Ring D is heterocycloalkenyl, aryl, or heteroaryl;
X 1 、X 2 and X 3 Independently CH or N;
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano; said heteroaryl is optionally further substituted with alkyl;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted with alkyl;
L 2 selected from oxygen atoms, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered monocyclic heterocyclic group, 6-14 membered fused heterocyclic group, or 6-14 membered bridged heterocyclic group;
ring C is heteroaryl;
R 2 selected from hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl;
R aa selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): ring D is heterocycloalkenyl, aryl, or heteroaryl.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): x 1 、X 2 And X 3 Independently CH or N.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): l is 1 Is selected fromAlkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): r 1 Selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano; the heteroaryl is optionally further substituted with alkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl is optionally further substituted with alkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): l is 2 Selected from an oxygen atom, or-NR 4 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): r is 4 Selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): l is a radical of an alcohol 3 is-NH-.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): and the ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered fused heterocyclic group or 6-14 membered bridged heterocyclic group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): ring C is heteroaryl.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): r 2 Selected from hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; the heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): r aa Selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), some groups are defined as follows (undefined groups are as defined above): r is 3 Selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): when ring D is a heterocycloalkenyl group, the heterocycloalkenyl group is preferably a 4-6 membered heterocycloalkenyl group in which "hetero atom (S) is (are) selected from one or more of N, O and S and the number of hetero atoms is 1-3" 3-8 membered heterocycloalkenyl group, more preferably "hetero atom (S) is (are) selected from one or more of N, O and S and the number of hetero atoms is 1-3", for example
Figure BDA0002321528230000471
In some embodiments of the present invention, in the compounds represented by the general formula (I-1), certain groups are defined as follows (undefined groups are as defined above): when ring D is an aryl group, the aryl group is preferably a 6-to 10-membered aryl group, more preferably a phenyl group.
In some embodiments of the present invention, a certain compound of the formula (I-1)The definitions of these groups are as follows (undefined groups are as indicated above): when ring D is a heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000472
Figure BDA0002321528230000481
Figure BDA0002321528230000482
More preferably
Figure BDA0002321528230000483
Figure BDA0002321528230000484
In some technical schemes of the invention, the compound shown as the formula (I) is preferably a compound shown as a formula (I-2),
Figure BDA0002321528230000485
wherein L is 1 、L 2 、L 3 、R 1 、R 2 、R 3 Ring B, ring C, y are as defined above;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above):
L 1 is alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R aa Selected from a hydrogen atom, or an alkyl group;
L 2 is-NH-;
L 3 is-NH-;
ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 is alkyl, cyano, heterocyclyl, or heteroaryl; said heterocyclyl is optionally further substituted by cyano;
R 2 Selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above):
L 1 is alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-(CH 2 ) n1 S(O) m1 -；
R aa Selected from a hydrogen atom, or an alkyl group;
L 2 is-NH-;
L 3 is-NH-;
ring B is selected from 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 is alkyl, cyano, or heterocyclyl;
R 2 selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above):
L 1 is C 1 -C 4 Alkylene of (a) - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-(CH 2 ) n1 S(O) m1 -；
R aa Selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
L 2 is-NH-;
L 3 is-NH-;
the ring B is selected from 7-10 membered bridged heterocyclic group with 1-3 heteroatoms selected from one or more of N, O and S, or 7-10 membered fused heterocyclic group with 1-3 heteroatoms selected from one or more of N, O and S;
the ring C is a 5-6-membered monoheteroaryl group of which the heteroatom is selected from one or more of N, O and S and the number of the heteroatoms is 1-3;
R 1 Is C 1 -C 4 The "hetero atom" is one or more selected from N, O and S, and the number of hetero atoms is 1 to 3 ";
R 2 selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
R 3 selected from hydrogen atoms, C 1 -C 3 Alkyl of, or C 1 -C 3 Hydroxyalkyl of (b);
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when L is 1 When it is an alkylene group, said alkylene group is preferably C 1 -C 4 Alkylene of, e.g. -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, more preferably-CH 2 -, or- (CH) 2 ) 2 -。
In some embodiments of the present invention, a certain compound of the formula (I-2)The definitions of these groups are as follows (undefined groups are as indicated above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 When said- (CH) 2 ) n1 C(O)(CH 2 ) m1 -preferably-C (O) -, -C (O) CH 2 -, or-CH 2 C(O)-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 When is- (CH) of 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -preferably-C (O) CH 2 NH-、-C(O)CH 2 N(CH 3 ) -, or-CH 2 C(O)N(CH 3 )-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 S(O) m1 When said- (CH) 2 ) n1 S(O) m1 -preferably-S (O) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), certain groups are defined as follows (undefined groups are as defined above): when R is aa When alkyl, the alkyl is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), certain groups are defined as follows (undefined groups are as defined above): when said ring B is a 3-10 membered heteromonocyclic group, said 3-10 membered heteromonocyclic group is preferably "a hetero atom is selected from one or more of N, O and S, a 3-to 8-membered heteromonocyclic group having 1 to 4 hetero atoms, more preferably" the hetero atom is selected from the group consisting of N,one or more of O and S, a 4-6 membered heteromonocyclic group having 1 to 3 "hetero atoms, e.g.
Figure BDA0002321528230000501
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when the ring B is a 6-14-membered bridged heterocyclic group, the 6-14-membered bridged heterocyclic group is preferably a 6-14-membered bridged heterocyclic group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 7-10-membered bridged heterocyclic group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000502
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when the ring B is a 6-14-membered fused heterocyclic group, the 6-14-membered fused heterocyclic group is preferably a 6-14-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000511
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when the ring C is a heteroaryl group, the heteroaryl group is preferably a 6-to 14-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4" heteroatoms, more preferably a 5-to 6-membered monoheteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3" heteroatoms, or an 8-to 10-membered fused heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3" heteroatoms. The 5-to 6-membered monoheteroaryl group is preferably
Figure BDA0002321528230000512
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When alkyl, the alkyl is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), certain groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000513
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of a heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000514
Figure BDA0002321528230000515
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined) The groups of (a) are as previously shown): when said R is 2 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), some groups are defined as follows (undefined groups are as defined above): when said R is 3 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-2), certain groups are defined as follows (undefined groups are as defined above): when said R is 3 In the case of hydroxyalkyl, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Hydroxyalkyl of (2), further preferably C 1 -C 3 The hydroxyalkyl group of (2) is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxyisopropyl group, and a hydroxymethyl group is further preferred.
In some technical schemes of the invention, the compound shown in the formula (I) is preferably a compound shown in a formula (I-3),
Figure BDA0002321528230000521
wherein L is 1 、L 2 、L 3 、R 1 、R 2 、R 3 Ring B, ring C and y are as defined above;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above):
L 1 is alkylene, - (CH 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Is an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 is hydrogen, alkyl, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said heterocyclyl or heteroaryl is optionally further substituted with unsubstituted alkyl or cyano; said aryl group is optionally further substituted with an unsubstituted alkoxy group;
R 2 selected from a hydrogen atom, an alkyl group, a heterocyclic group, or- (CH) 2 ) n1 SR aa (ii) a Said alkyl is optionally further substituted with unsubstituted alkoxy, or alkyl substituted or unsubstituted heterocyclyl; said heterocyclyl is optionally further substituted by alkyl;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
R aa selected from a hydrogen atom, or an alkyl group;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above):
L 1 Is alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Is an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 1 is a hydrogen atom, an alkyl group, a cyano group, a heterocyclic group, or a heteroaryl group; said heterocyclyl or heteroaryl group is optionally further substituted with unsubstituted alkyl, or cyano;
R 2 selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group;
R aa selected from a hydrogen atom, or an alkyl group;
x is 0, 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above):
L 1 is C 1 -C 4 Alkylene of (a) - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Is an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
L 3 is-NH-;
the ring B is selected from a 4-6 membered heteromonocyclic group with one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, a 7-10 membered bridged heterocyclic group with one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, or a 7-10 membered fused heterocyclic group with one or more heteroatoms selected from N, O and S and 1-3 heteroatoms;
The ring C is a 5-6-membered monoheteroaryl group of which the heteroatom is selected from one or more of N, O and S and the number of the heteroatoms is 1-3;
R 1 is a hydrogen atom, C 1 -C 3 A 4-6 membered heteromonocyclic group having 1-3 hetero atoms selected from one or more of N, O and S, or a 5-6 membered heteroaryl group having 1-3 hetero atoms selected from one or more of N, O and S; said mono-or heteroaryl being optionally further substituted by C 1 -C 3 Alkyl, or cyano of (a);
R 2 selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
R 3 selected from hydrogen atoms, C 1 -C 3 Alkyl of (2), or C 1 -C 3 Hydroxyalkyl groups of (a);
R aa selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
x is 0, 1 or 2.
Preferably:
L 1 is alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -, or- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -；
R 1 Is alkyl, cyano, heterocyclyl or heteroaryl; said heterocyclyl is optionally further substituted with alkyl;
L 2 is an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is a 6-14 membered bridged heterocyclic group;
ring C is heteroaryl;
R 2 selected from a hydrogen atom, or an alkyl group;
R 3 selected from a hydrogen atom, or an alkyl group;
R aa selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when it is at home L is 1 When it is an alkylene group, said alkylene group is preferably C 1 -C 4 Alkylene of, e.g. -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, more preferably-CH 2 -, or- (CH) 2 ) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 When is- (CH) of 2 ) n1 C(O)(CH 2 ) m1 -preferably-C (O) -, -C (O) CH 2 -, or-CH 2 C(O)-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 When is- (CH) of 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -preferably-C (O) CH 2 NH-、-C(O)CH 2 N(CH 3 )-、-C(O)CH 2 NHCH 2 -、-C(O)CH 2 NH(CH 2 ) 2 -, or-CH 2 C(O)N(CH 3 )-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 S(O) m1 When is- (CH) of 2 ) n1 S(O) m1 -preferably-S (O) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 4 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Alkyl of (2) furtherPreferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when ring B is a 3-to 10-membered heteromonocyclic group, the 3-to 10-membered heteromonocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000551
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when ring B is a 6-14-membered bridged heterocyclic group, the 6-14-membered bridged heterocyclic group is preferably a 6-14-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000552
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when the ring B is a 6-14-membered fused heterocyclic group, the 6-14-membered fused heterocyclic group is preferably a 6-14-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000553
In some embodiments of the present invention, the compound represented by the general formula (I-3)In the compounds, certain groups are defined as follows (undefined groups are as indicated above): when the ring C is a heteroaryl group, the heteroaryl group is preferably a 6-to 14-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered monoheteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000561
Figure BDA0002321528230000562
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said R is 1 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When it is an alkoxy group, the alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When cycloalkyl is said cycloalkyl is preferably C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000563
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000564
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When aryl, the aryl group is preferably a 6-to 10-membered aryl group, more preferably a phenyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of the heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000571
Figure BDA0002321528230000572
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when the heterocyclyl, or heteroaryl is optionally further substituted with an alkyl, the alkyl is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 Alkyl of (2), e.g. methyl, ethylPropyl or isopropyl, and methyl is more preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said aryl group is optionally further substituted with an alkoxy group, said alkoxy group is preferably C 1 -C 8 Alkoxy of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000573
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is- (CH) 2 ) n1 SR aa When said- (CH) 2 ) n1 SR aa Preference is given to
Figure BDA0002321528230000574
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 When the alkyl group is optionally further substituted with an unsubstituted, unsubstituted alkoxy group, the alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When the alkyl group is an alkyl group, said alkyl group being optionally further substituted with a substituted or unsubstituted heterocyclic group, said heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000581
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said heterocyclyl is optionally further substituted by alkyl, said alkyl is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 3 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is 3 In the case of hydroxyalkyl, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The hydroxyalkyl group of (2) is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxyisopropyl group, and a hydroxymethyl group is further preferred.
In some embodiments of the present invention, in the compounds represented by the general formula (I-3), some groups are defined as follows (undefined groups are as defined above): when said R is aa When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, the compound represented by the general formula (I) may be a compound represented by the following formula (I-4):
Figure BDA0002321528230000591
wherein L is 1 Selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, alkoxy, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted by alkyl;
L 2 、L 3 、R 2 、R 3 ring B, ring C, x and y are as previously defined.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above):
L 1 selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, alkoxy, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted by alkyl;
L 2 is-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
Ring C is heteroaryl;
R 2 selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 OR cc Or is- (CH) 2 ) n1 NR aa R bb (ii) a Said alkyl is optionally further substituted by alkylSubstituted or unsubstituted heterocyclyl; said alkoxy group is optionally further substituted with an unsubstituted alkoxy group, an alkyl substituted or unsubstituted heterocyclyl group, or an unsubstituted heteroaryl group; said heterocyclyl is optionally further substituted with an amino group selected from unsubstituted alkyl, unsubstituted alkoxy, or alkyl; said heteroaryl is optionally further substituted with a substituent selected from the group consisting of halogen substituted or unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, or an alkyl group; said alkyl is optionally further substituted with a heterocyclic group selected from alkyl substituted or unsubstituted, or unsubstituted heteroaryl;
R cc is a heterocyclic group; said heterocyclyl is optionally further substituted by unsubstituted alkyl;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above):
L 1 Selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo or alkoxy; said heterocyclyl is optionally further substituted by cyano; said heteroaryl is optionally further substituted with alkyl;
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 -，R 1 Is alkyl, heterocyclyl, or heteroaryl; said alkyl is optionally further substituted with halo; said heterocyclyl or heteroaryl being optionally further substituted by alkyl;
L 2 is-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is-NH-;
ring B is selected from 3-10 membered single heterocyclic group, 6-14 membered bridged heterocyclic group, or 6-14 membered fused heterocyclic group;
ring C is heteroaryl;
R 2 selected from hydrogen, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl;
R 3 selected from a hydrogen atom, an alkyl group, or a hydroxyalkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above):
L 1 is selected from C 1 -C 4 Alkylene of (a) - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Selected from halogen, cyano, C 1 -C 3 An "alkyl group having 4 to 6-membered heteromonocyclic group having 1 to 3" hetero atoms selected from one or more of N, O and S, or a "5 to 6-membered monoheteroaryl group having 1 to 3" hetero atoms selected from one or more of N, O and S; said C 1 -C 3 Optionally further substituted by halogen or C 1 -C 3 Substituted with an alkoxy group of (a); said heterocyclyl is optionally further substituted by cyano; said heteroaryl is optionally further substituted by C 1 -C 3 Alkyl of (a);
when L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 When is, R 1 Is C 1 -C 3 An "heteroatom selected from one or more of N, O and S, a 4-6 membered heteromonocyclic group having 1-3 heteroatoms", or a "heteroatom selected from N, O andone or more of S, 5-6 membered monoheteroaryl with 1-3 heteroatoms; said C 1 -C 3 Optionally further substituted with halogen; said heterocyclyl or heteroaryl being optionally further substituted by C 1 -C 3 Is substituted with an alkyl group of (a);
L 2 is-NR 4 -；
R 4 Selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
L 3 is-NH-;
ring B is selected from a 4-6 membered heteromonocyclic group having 1-3 hetero atoms selected from one or more of N, O and S, a 7-10 membered bridged heterocyclic group having 1-3 hetero atoms selected from one or more of N, O and S, or a 7-10 membered fused heterocyclic group having 1-3 hetero atoms selected from one or more of N, O and S;
The ring C is a 5-6-membered monoheteroaryl group of which the heteroatom is selected from one or more of N, O and S and the number of the heteroatoms is 1-3;
R 2 selected from hydrogen atoms, C 1 -C 3 Alkyl of (C) 1 -C 3 Alkoxy, halogen, cycloalkyl, "4-6 membered heteromonocyclic group with hetero atom selected from one or more of N, O and S, 1-3" hetero atom, 6-10 membered aryl, or "5-6 membered heteroaryl with hetero atom selected from one or more of N, O and S, 1-3" hetero atom; said heteroaryl is optionally further selected from unsubstituted C 1 -C 3 Alkyl of (2), unsubstituted C 1 -C 3 Substituted by 4-6 membered heteromonocyclic group with 1-3 hetero atoms, or one or more of N, O and S;
R 3 selected from hydrogen atom, C 1 -C 3 Alkyl of, or C 1 -C 3 Hydroxyalkyl of (b).
L 1 Is alkylene, or- (CH) 2 ) n1 S(O) m1 -；
R 1 Is cyano, or heterocyclyl; said heterocyclyl is optionally further substituted by cyano;
L 2 is-NH-;
L 3 is-NH-;
R 2 selected from a hydrogen atom, a halogen, or an alkoxy group;
R 3 selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 When it is an alkylene group, said alkylene group is preferably C 1 -C 4 Alkylene of, e.g. -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, more preferably-CH 2 -, or- (CH) 2 ) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 When said- (CH) 2 ) n1 C(O)(CH 2 ) m1 -preferably-C (O) -, -C (O) CH 2 -, or-CH 2 C(O)-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 When said- (CH) 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -preferably-C (O) CH 2 NH-, or-C (O) CH 2 N(CH 3 )-。
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said L is 1 Is- (CH) 2 ) n1 S(O) m1 When is- (CH) of 2 ) n1 S(O) m1 -preferably-S (O) 2 -。
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 4 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when the ring B is a 3-to 10-membered heteromonocyclic group, the 3-to 10-membered heteromonocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000622
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when ring B is a 6-14-membered bridged heterocyclic group, the 6-14-membered bridged heterocyclic group is preferably a 6-14-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 7-10-membered bridged heterocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000621
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when the ring B is a 6-14-membered fused heterocyclic group, the 6-14-membered fused heterocyclic group is preferably a 6-14-membered fused heterocyclic group having "one or more hetero atoms selected from N, O and S, the number of hetero atoms being 1 to 4", more preferably " Hetero atoms selected from one or more of N, O and S, 7-to 10-membered fused heterocyclic groups having 1 to 3 hetero atoms, e.g.
Figure BDA0002321528230000631
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when the ring C is a heteroaryl group, the heteroaryl group is preferably a 6-to 14-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered monoheteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000632
Figure BDA0002321528230000633
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When halogen is used, fluorine is preferred as the halogen.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 1 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 1 When it is an alkoxy group, said alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and further preferably a methoxy group or an ethoxy group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000634
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 1 In the case of a heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000641
Figure BDA0002321528230000642
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are as defined inShown below (undefined groups as indicated above): when said R is 2 When it is an alkoxy group, said alkoxy group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and further preferably a methoxy group or an ethoxy group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 When halogen is used, the halogen is preferably fluorine, chlorine or bromine.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 In the case of a heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000643
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When aryl, the aryl group is preferably a 6-to 10-membered aryl group, and more preferably a phenyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 In the case of a heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000644
Figure BDA0002321528230000645
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is- (CH) 2 ) n1 NR aa R bb When said- (CH) 2 ) n1 NR aa R bb Preference is given to
Figure BDA0002321528230000651
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When the alkyl group is an alkyl group, said alkyl group being optionally further substituted with a substituted or unsubstituted heterocyclic group, said heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "a hetero atom selected from one or more of N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000652
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 Is an alkoxy group, said alkoxy group being optionally further substituted with an unsubstituted alkoxy group, said unsubstituted alkoxy group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined As shown below (undefined groups as indicated above): when said R is 2 When the alkoxy group is optionally further substituted with an alkyl-substituted or unsubstituted heterocyclic group, the heterocyclic group is preferably a 3-to 8-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 4 hetero atoms", more preferably a 4-to 6-membered heteromonocyclic group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", for example
Figure BDA0002321528230000653
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When the alkoxy group is optionally further substituted with an alkyl-substituted or unsubstituted heterocyclic group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 When the alkoxy group is optionally further substituted with an unsubstituted heteroaryl group, the heteroaryl group is preferably a 5-to 10-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms", for example
Figure BDA0002321528230000654
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted by unsubstituted alkyl, orThe alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted by an unsubstituted alkoxy group, said alkoxy group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), certain groups are defined as follows (undefined groups are as defined above): when said R is 2 Is a heterocyclic group, said heterocyclic group being optionally further substituted by an amino group substituted by an alkyl group, said alkyl group preferably being C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is heteroaryl, said heteroaryl being optionally further substituted with a halogen-substituted or unsubstituted alkyl, said alkyl preferably being C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 When heteroaryl is optionally further substituted with halogen-substituted or unsubstituted alkyl, the halogen is preferably fluorine.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is heteroaryl, said heteroaryl being optionally further substituted with unsubstituted alkoxy, said alkoxy preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkoxy group of (2) is, for example, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and a methoxy group is further preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 2 Is heteroaryl, said heteroaryl being optionally further substituted by unsubstituted cycloalkyl, preferably said cycloalkyl is C 3 -C 8 Cycloalkyl of (2), more preferably C 3 -C 6 Cycloalkyl radicals, e.g.
Figure BDA0002321528230000661
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is aa And R bb When independently an alkyl group, said alkyl group is preferably C 1 -C 8 Alkyl of (2), more preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is aa And R bb Independently an alkyl group optionally further substituted with an alkyl-substituted or unsubstituted heterocyclyl group In the case where the heterocyclic group is mentioned, it is preferable that "hetero atom (S) is (are) selected from one or more of N, O and S, and 3-to 8-membered heteromonocyclic group having 1 to 4 hetero atom (S)", more preferable that "hetero atom (S) is (are) selected from one or more of N, O and S, and 4-to 6-membered heteromonocyclic group having 1 to 3 hetero atom (S)", for example
Figure BDA0002321528230000671
Figure BDA0002321528230000672
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is aa And R bb Independently an alkyl group, said alkyl group being optionally further substituted with an alkyl-substituted or unsubstituted heterocyclyl group, said alkyl group preferably being C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is aa And R bb Independently an alkyl group, said alkyl group optionally being further unsubstituted heteroaryl, said heteroaryl preferably being a 5-to 10-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, with 1 to 4 heteroatoms", more preferably a 5-to 6-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, with 1 to 3 heteroatoms", for example
Figure BDA0002321528230000673
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 3 When it is an alkyl group, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The alkyl group of (2) is, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group, and a methyl group or an ethyl group is more preferable.
In some embodiments of the present invention, in the compounds represented by the general formula (I-4), some groups are defined as follows (undefined groups are as defined above): when said R is 3 In the case of hydroxyalkyl, the alkyl group is preferably C 1 -C 8 More preferably C 1 -C 6 Further preferably C 1 -C 3 The hydroxyalkyl group of (2) is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxyisopropyl group, and a hydroxymethyl group is further preferred.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000681
Figure BDA0002321528230000691
Figure BDA0002321528230000701
in some embodiments of the present invention, the compound of formula (I) may be a compound of formula (I-5):
Figure BDA0002321528230000711
wherein the content of the first and second substances,
R 2a is a hydrogen atom, a cyano group, an alkyl group or an alkoxy group;
R 2b is a hydrogen atom or a cyano group;
R 2c is a hydrogen atom or a halogen;
R 2d Is a hydrogen atom orA hydroxyl group;
n is 1 or 2;
L 1 、L 2 、L 3 、R 1 、R 3 ring C, y are as defined above.
In some technical schemes of the invention, the compound shown as the formula (I-5) is preferably a compound shown as a formula (I-5-1),
Figure BDA0002321528230000712
wherein n and R 2a 、R 2b 、R 2c And R 2d The definition of (c) is as described above.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000721
in some embodiments of the present invention, in the compounds represented by the general formula (I), some groups are defined as follows (undefined groups are as shown above):
L 3 selected from a bond, or-C (O) NR aa -；
R aa Selected from a hydrogen atom, or an alkyl group.
In some technical schemes of the invention, the compound shown in the formula (I) is preferably a compound shown in a formula (I-6),
Figure BDA0002321528230000722
wherein L is 2 Is selected from-NH-;
L 3 selected from a bond, or-C (O) NH-;
ring A is selected from 6-14 membered fused heteroaryl;
ring C is selected from heteroaryl;
y is 0, 1, 2 or 3;
n is 1 or 2.
In some embodiments of the present invention, the compound of formula (I) can be of the following structure,
Figure BDA0002321528230000731
in some embodiments of the present invention, the compound of formula (I) may be a compound of formula (I-7):
Figure BDA0002321528230000732
wherein ring C is heteroaryl and ring C is not
Figure BDA0002321528230000733
L 1 、L 2 、L 3 、R 1 、R 2 、R 3 Ring A, x and y are as defined above.
In some embodiments of the present invention, in the compounds represented by the general formula (I-7), certain groups are defined as follows (undefined groups are as defined above):
ring C is heteroaryl and ring C is not
Figure BDA0002321528230000734
L 1 Selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -, or- (CH) 2 ) n1 S(O) m1 -；
L 2 Selected from oxygen atoms, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is a hydrogen atom;
ring A is a 6-14 membered fused heteroaryl;
R 1 is a hydrogen atom, halogen, alkyl, cyano, or heterocyclic group; said heterocyclyl is optionally further substituted by cyano;
R 2 is a hydrogen atom;
R 3 selected from hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups, - (CH) 2 ) n1 C(O)NR aa R bb Or is- (CH) 2 ) n1 S(O) m1 NR aa R bb ；
R aa And R bb Independently selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, in the compounds represented by the general formula (I-7), certain groups are defined as follows (undefined groups are as defined above):
ring C is heteroaryl and ring C is not
Figure BDA0002321528230000741
L 1 Selected from alkylene, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -；
L 2 Selected from oxygen atoms, or-NR 4 -；
R 4 Selected from a hydrogen atom, or an alkyl group;
L 3 is a hydrogen atom;
ring A is a 6-14 membered fused heteroaryl;
R 1 is a hydrogen atom, halogen, alkyl, cyano, or heterocyclic group;
R 2 is a hydrogen atom;
R 3 selected from hydrogen atoms, alkyl groups, hydroxyalkyl groups, - (CH) 2 ) n1 C(O)NR aa R bb ；
R aa And R bb Independently selected from a hydrogen atom, or an alkyl group.
In some embodiments of the present invention, a certain compound of the formula (I-7)The definitions of these groups are as follows (undefined groups are as indicated above): when the ring C is a heteroaryl group, the heteroaryl group is preferably a 6-to 14-membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 4 heteroatoms", more preferably a 5-to 6-membered monoheteroaryl group having "one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms". The 5-to 6-membered monoheteroaryl group is preferably
Figure BDA0002321528230000742
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000743
Figure BDA0002321528230000751
in some embodiments of the present invention, the compound of formula (I) may be a compound of formula (I-8):
Figure BDA0002321528230000752
wherein R is 3a And R 3b Independently a hydrogen atom, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl or- (CH) 2 ) n1 C(O)NR aa R bb (ii) a Said alkyl, cycloalkyl or heterocyclyl is optionally further selected from the group consisting of halogen, hydroxy, unsubstituted alkyl;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, or an alkyl group;
when R is 3a When it is methyl, R 3b Is not a hydrogen atom;
R 1 、L 1 、L 2 and L 3 Are all defined asAs described above;
n is 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-8), some groups are defined as follows (undefined groups are as defined above):
R 3a and R 3b Independently a hydrogen atom, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl or- (CH) 2 ) n1 C(O)NR aa R bb (ii) a Said alkyl, cycloalkyl or heterocyclyl is optionally further selected from the group consisting of halogen, hydroxy, unsubstituted alkyl;
R aa and R bb Are the same or different and are each independently selected from a hydrogen atom, or an alkyl group;
when R is 3a When it is methyl, R 3b Is not a hydrogen atom;
L 1 selected from alkylene, or- (CH) 2 ) n1 S(O) m1 -；
L 2 is-NR 4 -；
L 3 is-NH-;
R 1 selected from cyano, or heterocyclyl; said heterocyclyl is optionally further substituted by cyano;
n is 1 or 2.
In some embodiments of the present invention, in the compounds represented by the general formula (I-8), some groups are defined as follows (undefined groups are as defined above):
R 3a and R 3b Independently a hydrogen atom, a halogen, an alkyl group, a hydroxyalkyl group, or a cycloalkyl group;
when R is 3a When it is methyl, R 3b Is not a hydrogen atom;
L 1 is selected from alkylene;
L 2 is-NH-;
L 3 is-NH-;
R 1 is cyano;
n is 1 or 2.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000771
in some embodiments of the present invention, in the compounds represented by the general formula (I), the compounds represented by the general formula (I) can be compounds represented by the following formula (I-9), and some groups are defined as follows (undefined groups are as shown above):
Figure BDA0002321528230000772
wherein ring B is selected from a 3-10 membered heteromonocyclic group, or a 6-14 membered fused heterocyclic group;
R 1 、R 3 、L 1 、L 2 、L 3 and y are as defined above.
In some embodiments of the present invention, in the compounds represented by the general formula (I-8), certain groups are defined as follows (undefined groups are as defined above):
ring B is selected from 3-10 membered monocyclic heterocyclic group, or 6-14 membered fused heterocyclic group;
L 1 selected from alkylene, or- (CH) 2 ) n1 S(O) m1 -；
L 2 is-NH-;
L 3 is-NH-;
R 1 selected from cyano, or heterocyclyl; said heterocyclyl is optionally further substituted by cyano;
R 3 selected from a hydrogen atom, or an alkyl group;
y is 0, 1 or 2.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000781
in some embodiments of the present invention, in the compounds represented by the general formula (I), the compounds represented by the general formula (I) may be compounds represented by the following formula (I-10), and some groups are defined as follows (undefined groups are as defined above):
Figure BDA0002321528230000782
Wherein L is 2 Selected from an oxygen atom, or-NR 4 -；
R 4 Is an alkyl group;
R 1 、R 3 、L 1 、L 3 and y are as defined above.
In some embodiments of the present invention, in the compounds represented by the general formula (I-10), certain groups are defined as follows (undefined groups are as defined above):
L 2 selected from an oxygen atom, or-NR 4 -；
R 4 Is an alkyl group;
L 1 selected from alkylene, or- (CH) 2 ) n1 S(O) m1 -；
L 3 is-NH-;
R 1 selected from cyano, or heterocyclyl; said heterocyclyl is optionally further substituted by cyano;
R 3 selected from a hydrogen atom, or an alkyl group;
y is 0, 1 or 2.
In some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000791
in some technical schemes of the invention, the compound shown as the formula (I) can be any one of the following structures,
Figure BDA0002321528230000792
Figure BDA0002321528230000801
Figure BDA0002321528230000811
Figure BDA0002321528230000821
Figure BDA0002321528230000831
Figure BDA0002321528230000841
Figure BDA0002321528230000851
Figure BDA0002321528230000861
Figure BDA0002321528230000871
Figure BDA0002321528230000881
Figure BDA0002321528230000891
Figure BDA0002321528230000901
the invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure BDA0002321528230000902
wherein:
L 1 selected from the group consisting of a bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of bonds, oxygen atoms, sulfur atoms, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -or-C (O) NR aa -；
Ring A is selected from 6-14 membered heteroaryl, wherein said 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; preferably 5 and 5-membered fused heteroaryl, 5 and 6-membered fused heteroaryl or 6 and 6-membered fused heteroaryl;
Ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered bridged heterocyclic group or 6-14 membered fused heterocyclic group;
ring C is selected from heteroaryl;
R 1 selected from the group consisting of a hydrogen atom, a deuterium atom, an oxo group, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an oxoheterocyclic group, and sulfurSubstituted heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb， Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 2 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxo group Heterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 3 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups A substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 4 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group;
R aa 、R bb 、R cc and R dd The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted or unsubstituted with a substituent selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitro group, cyano group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted, heteroaryl group, and, Substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;
x is an integer of 0, 1, 2 or 3;
y is an integer of 0, 1, 2, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
The invention also relates to a preferable scheme, the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is characterized in that,
wherein:
L 1 selected from the group consisting of a bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, -NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of a bond, an oxygen atom, a sulfur atom, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -or-C (O) NR aa -；
Ring A is selected from 6-14 membered heteroaryl, wherein said 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; preferably a 5 and 5 membered fused heteroaryl group, a 5 and 6 membered fused heteroaryl group or a 6 and 6 membered fused heteroaryl group;
ring B is selected from 6-14 membered bridged heterocyclic group or 6-14 membered fused heterocyclic group;
ring C is selected from heteroaryl;
R 1 selected from the group consisting of hydrogen atom, deuterium atom, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb， Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 2 a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an oxo group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, or an alkynyl group;
R 3 selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl and halogenAlkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group;
R aa 、R bb 、R cc and R dd The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl groups;
x is an integer of 0, 1, 2 or 3;
y is an integer of 0, 1, 2, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (II) and the general formula (IIA), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000951
wherein:
w is selected from a nitrogen atom or an alkylene group; and is
n is an integer of 0, 1, 2 or 3;
L 1 、L 2 、L 3 ring A, ring C, R 1 ～R 3 X and y are as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (IIIA), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000952
wherein:
R 5 selected from hydrogen atoms, halogens, cyano groups, alkyl groups, alkoxy groups, hydroxyalkyl groups, haloalkyl groups, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)NR aa R bb Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, - (CH) — (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 6 selected from hydrogen, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl or- (CH) 2 ) n1 C(O)NR aa R bb ；
L 1 、L 2 、L 3 Ring A, ring B, R 1 、R 2 And x is as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (III), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000961
wherein:
R 10 and R 11 The same or different, each independently selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb -, cycloalkyl, heterocyclyl, arylOr heteroaryl, wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
L 1 、L 2 、L 3 ring A, ring B, R 1 、R 2 And x is as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (IV), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000962
wherein:
ring D is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl or 5-6 membered heteroaryl;
E 1 、E 2 and E 3 Identical or different, each independently selected from nitrogen atoms or-CR aa -；
R 4 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl or alkoxy;
R 7 selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is
z is an integer of 0, 1, 2 or 3;
L 1 、L 3 ring C, R 1 、R 3 、R aa Y and n are as described in formula (I).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (V), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000971
wherein:
ring G is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl or 5-6 membered heteroaryl;
R 8 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is
p is an integer of 0, 1, 2 or 3;
R 5 and R 6 As claimed in claim 3;
L 1 、E 1 、E 2 、E 3 、R 4 and n is as described in formula (IV).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VI), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000972
wherein:
ring K is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl, 5-6 membered heteroaryl;
R 9 selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is provided with
q is an integer of 0, 1, 2 or 3;
R 5 and R 6 As claimed in claim 3;
E 1 、E 2 、E 3 and R 4 As described in general formula (IV).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VII), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000981
wherein:
n is an integer of 0, 1 or 2;
L 2 ring A, R 2 、R 5 、R 6 And x is as described in formula (IIIA).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (III), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VIII):
Figure BDA0002321528230000982
Wherein:
M 1 selected from nitrogen atoms or-CR aa -；
R 12 Selected from hydrogen atoms, cyano groups, halogens, alkyl groups or alkoxy groups; and is
z is an integer of 0, 1 or 2;
L 1 、L 2 ring C, R 1 、R 3 、R 7 、R aa And y is as described in formula (IV).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in a general formula (IX), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000991
wherein:
ring C, R 3 、R 12 、R 7 Y and z are as described in formula (VII).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (X), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000992
wherein:
R 5 ～R 6 as described in general formula (IIIA);
R 12 、R 7 and z is as described in formula (VII).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XI), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230000993
wherein:
L 1 、L 2 ring B, ring C, R 3 And R 12 As shown in the general formula (I)
R 7 Y and z are as described for formula (IX).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XII), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001001
Wherein:
L 1 selected from the group consisting of a bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
Ring B is selected from 3-10 membered heteromonocyclic group, 6-14 membered spiroheterocyclic group, 6-14 membered bridged heterocyclic group or 6-14 membered fused heterocyclic group;
ring T is selected from aryl or heteroaryl;
R 1 selected from the group consisting of hydrogen atom, deuterium atom, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 3 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, ammoniaAlkyl, nitro, hydroxyl, cyano, alkenyl, alkynyl;
R 13 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R aa 、R bb 、R cc and R dd The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl groups;
y is an integer of 0, 1, 2, 3, 4 or 5;
q is an integer of 0, 1, 2, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is provided with
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in a general formula (XIII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001021
wherein:
R 5 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, or heteroaryl group;
R 6 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, or heteroaryl group;
n is an integer of 0, 1 or 2;
L 1 ring T, R 1 、R 3 、R 4 、R 13 And q is as described in formula (XII).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XIV), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001031
Wherein:
L 1 、R 1 、R 4 ～R 6 、R 13 q and n are as described in formula (XIII).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XV), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001032
wherein:
L 1 selected from the group consisting of a bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, - (CH) 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
J 1 、J 2 And J 3 Identical or different, each independently selected from nitrogen atom, sulfur atom, oxygen atom, NR aa Or CR 14 ；
R 1 Selected from the group consisting of hydrogen atom, deuterium atom, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb， Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group;
R 5 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, or heteroaryl group;
R 6 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, or heteroaryl group;
R 14 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogenAmino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R aa 、R bb 、R cc and R dd The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl groups;
n is an integer of 0, 1 or 2;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XVI), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001051
wherein:
R 15 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy,Substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
L 1 、R 1 、R 5 ～R 6 、R aa ～R dd and n is as described in formula (XIV).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XVII), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001061
wherein:
R 16 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 O(CH 2 ) m1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa (CH 2 ) m1 R aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 S-、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, - (CH, or C 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
r is an integer of 0, 1 or 2; and is
L 1 、R 1 、R 4 ～R 6 、R aa ～R dd N, n1, m1 and m2 are as described for formula (XV).
The invention also relates to a preferable scheme, each general formula, the stereoisomer or the pharmaceutically acceptable salt thereof, which is characterized in that,
ring a is selected from the following groups:
Figure BDA0002321528230001071
Figure BDA0002321528230001081
ring B is selected from the following groups:
Figure BDA0002321528230001082
ring C is selected from the following groups:
Figure BDA0002321528230001083
the invention also relates to a preferable scheme, any one of the general formulas, the stereoisomers thereof or the pharmaceutically acceptable salts thereof is characterized in that,
L 1 is C 3-8 Cycloalkyl radical, C 3-8 Heterocycloalkyl, - (CH) 2 ) n1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 -、-(CH 2 ) n1 C(O)(CH 2 ) m1 NR aa (CH 2 ) m2 -、-NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of a bond, an oxygen atom, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -or-C (O) NR aa -；
R 1 Selected from cyano, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 C(O)R aa 、C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein said C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl optionally further substituted by one or more substituents selected from the group consisting of hydrogen, cyano, C 1-6 Alkyl radical, C 1-6 Substituted with one or more substituents of alkoxy;
R 2 hydrogen atom, halogen, cyano, hydroxy, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, - (CH) 2 ) n1 R aa 、-O(CH 2 ) n1 R aa 、-S(CH 2 ) n1 R aa or-NR aa (CH 2 ) n1 R bb Wherein said C 3-8 Cycloalkyl, 3-to 10-membered heterocyclic group, C 6-10 Aryl and 5-to 10-membered heteroaryl optionally further substituted by one or more substituents selected from the group consisting of hydrogen, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl or-NR cc R dd Is substituted with one or more substituents of (1);
R 3 selected from hydrogen atom, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl, 3-to 10-membered heterocyclyl, - (C)CH 2 ) n1 OR aa 、-C(O)NR aa R bb Or- (CH) 2 ) n1 S(O) m1 R aa Wherein said cycloalkyl and heterocyclyl are optionally further substituted by a hydrogen atom, C 1-6 Alkyl or hydroxy;
R 4 selected from a hydrogen atom or a methyl group;
R aa 、R bb 、R cc and R dd Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl, cyano, hydroxy, amino, C 3-8 Cycloalkyl, 3-to 10-membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said C 1-6 Alkyl radical, C 1-6 Haloalkyl, amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl optionally further substituted by hydrogen atom, cyano, hydroxy, amino, aminoalkyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl.
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound shown in the general formula (I) is as follows:
Figure BDA0002321528230001091
Wherein:
L 1 selected from the group consisting of a bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, -NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of bonds, oxygen atoms, sulfur atoms, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -or-C (O) NR aa -；
Ring A is selected from 6-14 membered heteroaryl, wherein said 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; preferably 5 and 5-membered fused heteroaryl, 5 and 6-membered fused heteroaryl or 6 and 6-membered fused heteroaryl;
ring B is selected from 6-14 membered bridged heterocyclic group or 6-14 membered fused heterocyclic group;
ring C is selected from heteroaryl;
R 1 selected from the group consisting of hydrogen atom, deuterium atom, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb， Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 NR cc C(O)R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
R 2 a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an oxo group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, or an alkynyl group;
R 3 selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, hydroxyalkyl group, heterocyclic group, oxoheterocyclic group, thioheterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 P(O) m2 R aa R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl areOptionally further substituted by a substituent selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitro group, cyano group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group, - (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group;
R aa 、R bb 、R cc and R dd The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted by a substituent selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group,Halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
x is an integer of 0, 1, 2 or 3;
y is an integer of 0, 1, 2, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2;
m 2 is an integer of 0, 1 or 2; and is
n 1 Is an integer of 0, 1, 2, 3, 4 or 5.
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (II) and the general formula (IIA), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001111
wherein:
w is selected from a nitrogen atom or an alkylene group; and is provided with
n is an integer of 0, 1, 2 or 3;
L 1 、L 2 、L 3 ring A, ring C, R 1 ～R 3 X and y are as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (IIIA), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001121
wherein:
R 5 selected from hydrogen atoms, halogens, cyano groups, alkyl groups, alkoxy groups, hydroxyalkyl groups, haloalkyl groups, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)NR aa R bb Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, - (CH) — (CH) 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 6 selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl or- (CH) 2 ) n1 C(O)NR aa R bb ；
L 1 、L 2 、L 3 Ring A, ring B, R 1 、R 2 And x is as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (III), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001122
wherein:
R 10 and R 11 The same or different, each independently selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb -, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, - (CH-), and 2 ) n1 -、-(CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 S(O) m1 NR cc R dd 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NR cc S(O) m1 R dd 、-(CH 2 ) n1 NR cc S(O) m1 R dd Or- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (a);
L 1 、L 2 、L 3 ring A, ring B, R 1 、R 2 And x is as described in formula (I).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (IV), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001131
wherein:
ring D is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl or 5-6 membered heteroaryl;
E 1 、E 2 and E 3 Identical or different, each independently selected from nitrogen atoms or-CR aa -；
R 4 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl or alkoxy;
R 7 selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is
z is an integer of 0, 1, 2 or 3;
L 1 、L 3 ring C, R 1 、R 3 、R aa Y and n are as described in formula (I).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (V), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001141
wherein:
ring G is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl or 5-6 membered heteroaryl;
R 8 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is provided with
p is an integer of 0, 1, 2 or 3;
R 5 and R 6 As claimed in claim 3;
L 1 、E 1 、E 2 、E 3 、R 4 and n is as described in formula (IV).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VI), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001142
wherein:
ring K is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl, 5-6 membered heteroaryl;
R 9 selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; and is
q is an integer of 0, 1, 2 or 3;
R 5 and R 6 As claimed in claim 3;
E 1 、E 2 、E 3 and R 4 As described in general formula (IV).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VII), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001151
wherein:
n is an integer of 0, 1 or 2;
L 2 ring A, R 2 、R 5 、R 6 And x is as described in formula (IIIA).
The invention also relates to a preferable scheme, the compound shown in the general formula (III), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (VIII), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001152
Wherein:
M 1 selected from nitrogen atoms or-CR aa -；
R 12 Selected from hydrogen atoms, cyano groups, halogens, alkyl groups or alkoxy groups; and is
z is an integer of 0, 1 or 2;
L 1 、L 2 ring C, R 1 、R 3 、R 7 、R aa And y is as described for formula (IV).
The invention also relates to a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in a general formula (IX), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001153
wherein:
ring C, R 3 、R 12 、R 7 Y and z are as described in formula (VII).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (X), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001161
wherein:
R 5 ～R 6 as described in general formula (IIIA);
R 12 、R 7 and z is as described in formula (VII).
The invention also relates to a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (XI), the stereoisomer thereof or the pharmaceutically acceptable salt thereof:
Figure BDA0002321528230001162
wherein:
L 1 、L 2 ring B, ring C, R 3 And R 12 As shown in the general formula (I)
R 7 Y and z are as described for formula (IX).
The invention also relates to a preferable scheme, each general formula, the stereoisomer or the pharmaceutically acceptable salt thereof, which is characterized in that,
Ring a is selected from the following groups:
Figure BDA0002321528230001163
Figure BDA0002321528230001171
ring B is selected from the following:
Figure BDA0002321528230001181
ring C is selected from the following groups:
Figure BDA0002321528230001182
the invention also relates to a preferable scheme, each general formula, the stereoisomer or the pharmaceutically acceptable salt thereof, which is characterized in that,
L 1 is C 3-8 Cycloalkyl radical, C 3-8 Heterocycloalkyl, - (CH) 2 ) n1 -、-NR aa (CH 2 ) n1 -、-(CH 2 ) n1 S(O) m1 -or- (CH) 2 ) n1 S(O) m1 NR aa -；
L 2 Selected from the group consisting of a bond, an oxygen atom, -CR aa R bb -、-(CH 2 ) n1 C(O)-、-NR 4 -or- (CH) 2 ) n1 S(O) m1 -；
L 3 Selected from the group consisting of a bond, -NR aa -or-C (O) NR aa -；
R 1 Selected from cyano, - (CH) 2 ) n1 R aa 、C 3-8 Cycloalkyl or 3-10 membered heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally further substituted by one or more substituents selected from the group consisting of hydrogen atom or cyano;
R 2 hydrogen atom, halogen, cyano, hydroxy, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy or 3-10 membered heterocyclyl; preferably hydrogen atom, halogen, cyano, hydroxy, oxo, C 1-3 Alkoxy radical, C 1-3 Alkyl or 3-8 membered heterocyclyl; more preferably a hydrogen atom, fluorine, cyano group, hydroxyl group, oxo group, methoxy group, methyl group or morpholinyl group;
R 3 selected from hydrogen atom, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl, 3-to 10-membered heterocyclyl, - (CH) 2 ) n1 OR aa 、-C(O)NR aa R bb Or- (CH) 2 ) n1 S(O) m1 R aa Wherein said cycloalkyl and heterocyclyl are optionally further substituted by a hydrogen atom, C 1-6 Alkyl or hydroxy;
R 4 Selected from a hydrogen atom or a methyl group;
R aa 、R bb 、R cc and R dd Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C 1-6 Alkyl, cyano, hydroxy, amino, or 3-10 membered heterocyclyl; wherein said C 1-6 The alkyl, amino and 3-10 membered heterocyclyl groups are optionally further substituted by one or more substituents selected from the group consisting of hydrogen, cyano, hydroxy and 5-10 membered heteroaryl.
The invention further relates to any of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or application of the pharmaceutical composition in preparation of JAK kinase inhibitor drugs.
The invention also relates to a method for the treatment, prevention and/or treatment of a condition mediated by a JAK kinase inhibitor, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also relates to a pharmaceutical composition, which comprises a therapeutically effective dose of the compound shown as the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also relates to the application of the compound of the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicaments for treating inflammatory diseases and tumor diseases.
The invention also relates to a method of treating an inflammatory disease selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease, and a method of treating a neoplastic disease comprising administering to a patient a therapeutically effective dose of a pharmaceutical composition; wherein the gastrointestinal inflammatory disease is chronic intestinal inflammatory disease, preferably ulcerative colitis and Crohn's disease.
The invention also relates to a method of treating a neoplastic disease selected from the group consisting of myelofibrosis, polycythemia vera, and essential thrombocythemia, myeloid leukemia (AML), acute Lymphocytic Leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSCLC), comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition.
The invention also relates to a pharmaceutical composition, which comprises the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof can be used in a therapeutically effective amount.
The invention further relates to an application of any compound shown as the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of JAK kinase inhibitors.
The invention also relates to application of the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of medicines for preventing and/or treating JAK kinase-related diseases. The JAK kinase-associated disease is preferably an inflammatory disease and/or a neoplastic disease; the inflammatory disease is preferably selected from rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease; wherein the gastrointestinal inflammatory disease is preferably chronic intestinal inflammatory disease, and more preferably ulcerative colitis and Crohn's disease. The tumor disease is preferably selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of mammary gland and non-small cell lung cancer.
The invention also relates to the application of the compound with the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicaments, wherein the medicaments are preferably medicaments for treating inflammatory diseases and/or tumor diseases. The inflammatory disease is preferably selected from rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease; wherein the gastrointestinal inflammatory disease is chronic intestinal inflammatory disease, preferably ulcerative colitis and Crohn's disease. The tumor disease is preferably selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of mammary gland and non-small cell lung cancer.
The invention also relates to a method for treating inflammatory diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the inflammatory diseases are selected from rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel diseases; wherein the gastrointestinal inflammatory disease is chronic intestinal inflammatory disease, further preferably ulcerative colitis and Crohn's disease.
The invention also relates to a method for treating a neoplastic disease selected from the group consisting of myelofibrosis, polycythemia vera and essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of the breast and non-small cell lung cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also relates to a method for preventing and/or treating a condition mediated by a JAK kinase, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. Said JAK kinase-mediated condition is preferably an inflammatory disease and/or a neoplastic disease; the inflammatory disease is preferably selected from rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease; wherein the gastrointestinal inflammatory disease is preferably chronic intestinal inflammatory disease, and more preferably ulcerative colitis and Crohn's disease. The tumor disease is preferably selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of mammary gland and non-small cell lung cancer.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH 2 -, "ethylene" means- (CH) 2 ) 2 -, "propylene" means- (CH) 2 ) 3 -, "butylene" means- (CH) 2 ) 4 -and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, with cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl groups being preferred, and cyclopropyl, cyclobutyl and cyclopentyl groups being more preferred.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0002321528230001221
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure BDA0002321528230001222
the term "fused ring alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 5-membered/5-membered, or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0002321528230001223
The term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0002321528230001224
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen, boron, phosphorus, S (O) m (wherein m is an integer of 0 to 2) or P (O) n (wherein n is an integer from 0 to 2) but does not include the ring portion of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, and pyranyl being preferred. More preferably azetidinyl, oxetanylButyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperidinyl, and piperazinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to 3 to 20 membered polycyclic heterocyclic groups in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more of the ring atoms is nitrogen, oxygen, boron, phosphorus, S (O) m (wherein m is an integer of 0 to 2) or P (O) n (wherein n is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiro heterocyclyl groups include:
Figure BDA0002321528230001231
Figure BDA0002321528230001232
and the like.
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-to 5-membered 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0002321528230001241
Figure BDA0002321528230001242
and the like.
The term "bridged heterocyclyl" refers to 5 to 14 membered polycyclic heterocyclic group wherein any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0002321528230001243
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0002321528230001244
Figure BDA0002321528230001251
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0002321528230001252
Figure BDA0002321528230001253
and the like.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, pyridazinyl and the like, preferably pyrazinyl, pyridazinyl, oxazolyl, oxadiazole, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazole, pyrazolyl and pyrimidinyl; more preferred are pyrazinyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, triazolyl, pyrazolyl and thiazolyl.
The term "fused heteroaryl" refers to a heteroaromatic system comprising 1 to 6 heteroatoms, 4 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Fused heteroaryl is preferably 6 to 14 membered, more preferably 6 or 10 membered said fused heteroaryl ring means that the heteroaryl is fused to an aryl, heterocyclyl or cycloalkyl ring, non-limiting examples of which include:
Figure BDA0002321528230001261
Figure BDA0002321528230001271
the heteroaryl or fused heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" means (CH.ident.C-or-C.ident.C-), wherein said alkynyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" means-CN.
"nitro" means-NO 2 。
"carboxy" means-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"AN" refers to acrylonitrile.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "means diethyl ether.
"DCE" refers to 1, 2-dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B and C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compounds of the examples related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity. "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gi min i C18X 4.6mm column).
The thin layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by a thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent and the reaction temperature is given in degrees celsius.
Example 1
3- ((3-exo) -3- ((7- ((5-methylthiooxazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001301
The first step is as follows: tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001302
The compound 5, 7-dichloro-1, 6-naphthyridine (100mg, 0.502mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (119mg, 0.527 mmol) and diisopropylethylamine (195mg, 1.51mmol) were dissolved in dimethyl sulfoxide (4 mL), and the reaction mixture was heated to 110 ℃ and stirred for reaction for 22 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give the title compound as an off-white solid (173mg, 92%).
1 H NMR(400MHz,DMSO-d 6 )δ8.89(dd,J＝4.2,1.3Hz,1H),8.72(d,J＝8.3Hz,1H),7.74(d,J＝7.5Hz,1H),7.48(dd,J＝8.4,4.3Hz,1H),6.96(s,1H),4.70-4.56(m,1H),4.16(s,2H),2.05-1.87(m,4H),1.81-1.57(m,4H),1.44(s,9H).
MS m/z(ESI):389.2[M+H] + .
The second step is that: preparation of 3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001311
Tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.257mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added with stirring at room temperature, the resulting reaction mixture was stirred at room temperature for 30 minutes, the solvent was removed by concentration under reduced pressure, anhydrous methanol was added and dissolved, then diisopropylethylamine (332mg, 2.57mmol) and acrylonitrile (1695, 0.31mmol) were added in this order, the reaction mixture was stirred at room temperature for 26.5 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a white powder (81mg, 92%).
1 H NMR(400MHz,DMSO-d 6 )δ8.90-8.87(m,1H),8.72(d,J＝8.3Hz,1H),7.76(d,J＝7.7Hz,1H),7.47(dd,J＝8.4,4.3Hz,1H),6.94(s,1H),4.51-4.35(m,1H),3.34(s,2H),2.69-2.58(m,4H),1.98-1.88(m,2H),1.84-1.62(m,6H).
MS m/z(ESI):342.1[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methylthiooxazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001312
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.146mmol), 5-methylthiooxazol-2-amine (25mg, 0.219mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (7mg, 0.009mmol) and cesium carbonate (86mg, 0.263mmol) were added to super-dried 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen and the vial was heated to 110 ℃ with stirring for 24 hours, then cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the title compound was isolated by preparative TLC as a yellow-green solid (14mg, 23%).
1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),8.71-8.63(m,1H),8.55(d,J＝8.3Hz,1H),7.47(d,J＝8.6Hz,1H),7.10(dd,J＝8.3,4.3Hz,1H),7.02(d,J＝1.1Hz,1H),6.46(s,1H),4.96-4.77(m,1H),3.36(s,2H),2.65(s,4H),2.32(s,3H),2.04-1.72(m,8H).
MS m/z(ESI):420.2[M+H] + .
Example 2
3- (3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001321
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) propionitrile (50mg, 0.146mmol), (2-aminothiazol-5-yl) methanol (38mg, 0.292mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (58mg, 0.073mmol) and cesium carbonate (143mg, 0.438mmol) were added to ultradry 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen and deoxygenated, then heated to 140 ℃ with a microwave reactor, stirred for 2.5 hours and cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the title compound (8.6mg, 14%) was isolated and purified by silica gel column chromatography and reverse phase HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ10.85(s,1H),8.70-8.65(m,1H),8.60-8.53(m,1H),7.47(d,J＝8.6Hz,1H),7.18(s,1H),7.11(dd,J＝8.3,4.3Hz,1H),6.50(s,1H),5.16(t,J＝5.2Hz,1H),4.86(dd,J＝16.7,8.2Hz,1H),4.56(d,J＝5.2Hz,2H),3.33(s,2H),2.65(s,4H),1.99-1.86(m,4H),1.81(d,J＝7.4Hz,4H).
MS m/z(ESI):436.1[M+H] + .
Example 3
3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7 hydro-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001331
The first step is as follows: preparation of 2, 4-dichloro-5-tosyl-7 h-pyrrolo [2,3-d ] pyrimidine
Figure BDA0002321528230001332
To a solution of 2, 4-dichloropyrrolo [3,2-D ] pyrimidine (200mg, 1.06mmol) in methylene chloride (5 mL) were added TsCl (242mg, 1.27mmol), DIPEA (273mg, 2.12mmol) in this order, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was extracted with DCM (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (PE: DCM from 0 to 70) to obtain the title compound as a white solid (360mg, 99%).
MS m/z(ESI):343.0[M+H] + .
The second step is that: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) -7-tosyl-7-hydro-pyrrolo [2,3-d ] pyrimidin-4-amine
Figure BDA0002321528230001333
To a solution of 2, 4-dichloro-5-toluenesulfonyl-7 h-pyrrolo [2,3-d ] pyrimidine (171mg, 0.5 mmol) in MeCN (10 mL) was added 3-amino-5-methylpyrazole (53mg, 0.55mmol), DIPEA (129mg, 1mmol) in that order, followed by stirring at 100 ℃ for 2 hours under microwave conditions. At the end of the reaction, the reaction solution was extracted with EA (15mL × 3), washed with saturated aqueous sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (DCM: meOH from 0 to 95) to obtain the title compound as a pale yellow solid (185mg, 92%).
MS m/z(ESI):402.1[M+H] + .
The third step: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7-toluenesulfonyl-7 hydro-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid
Figure BDA0002321528230001341
To a solution of 2-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) -7-tosyl-7 hydro-pyrrolo [2,3-d ] pyrimidin-4-amine (100mg, 0.25mmol) in N-BuOH (5 mL) was added N-Boc-exo-3-aminotropane (85mg, 0.375mmol), DIPEA (64.5mg, 0.5mmol) in this order, followed by stirring at 150 ℃ for 12 hours under microwave conditions. After completion of the reaction, the reaction mixture was extracted with EA (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound as a pale yellow solid (100mg, 68%).
MS m/z(ESI):593.1[M+H] + .
The fourth step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001342
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7-tosyl-7 hydro-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid (100mg, 0.17mmol) was dissolved in ethyl acetate hydrochloride solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was spin-dried; meOH (10 mL) was then added to dissolve it, DIPEA (88mg, 0.68mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (14mg, 0.26mmol) was added followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: meOH = 10) to give the title compound as a yellow solid (52.6mg, 57%).
MS m/z(ESI):546.1[M+H] + .
The fifth step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7 hydro-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001351
To a mixed solution of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7-toluenesulfonyl-7 hydro-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) propionitrile (50mg, 0.09mmol) in 1, 4-dioxane (10 mL) and methanol (5 mL) was added an aqueous solution (0.2 mL) of sodium hydroxide (36mg, 0.9 mmol), which was then stirred at 55 ℃ overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the title compound was obtained as a white solid (10mg, 29%) by prep-HPLC.
1 H NMR(400MHz,DMSO)δ11.85(s,1H),10.72(s,1H),9.38(s,1H),6.67(s,3H),5.92(s,1H),4.11(s,1H),3.29(s,2H),2.62(s,4H),2.20(s,3H),1.90(s,2H),1.82-1.47(m,6H).
MS m/z(ESI):392.2[M+H] + .
Example 4
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001352
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0002321528230001353
2, 4-dichloroquinazoline (199mg, 1.0 mmol), 5-methyl-1H-pyrazol-3-amine (99mg, 1.02mmol) and triethylamine (213mg, 2.1mmol) were added to absolute ethanol (5 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was suspended in water-ethanol (v \ v = 9.
MS m/z(ESI):260.1,262.1[M+H] + .
The second step is that: tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001361
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (40mg, 0.154mmol) and tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (70mg, 0.308mmol) were added to N-butanol (3 mL), and after stirring well at room temperature, the reaction was carried out at 150 ℃ for 4 hours under microwave conditions. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give the crude title compound (120 mg) which was used directly in the next reaction.
MS m/z(ESI):450.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001362
Crude tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (120mg, 0.154mmol) was dissolved in methanol (3 mL), 4M HCl in 1, 4-dioxane (10 mL) was added with stirring at room temperature, the resulting reaction mixture was stirred with stirring at room temperature for 30 minutes, the solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous methanol (10 mL), diisopropylethylamine (0.51mL, 3.08mmol) and acrylonitrile (10mg, 0.154mmol) were sequentially added with stirring at room temperature, the resulting reaction mixture was stirred at room temperature for 2.5 hours, the solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography and reverse phase HPLC to give the title compound (6.0mg, 10%).
1 H NMR(400MHz,CD 3 OD)δ8.04(d,J＝8.1Hz,1H),7.58(t,J＝7.5Hz,1H),7.39(s,1H),7.16(t,J＝7.5Hz,1H),6.62(s,1H),4.35(s,1H),3.37(s,2H),2.76(t,J＝6.9Hz,2H),2.62(t,J＝6.9Hz,2H),2.31(s,3H),2.16-1.74(m,6H),1.67(t,J＝11.7Hz,2H).
MS m/z(ESI):403.2[M+H] + .
Example 5
3- (cis-5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0002321528230001371
The first step is as follows: preparation of tert-butyl (3aR, 5r, 6aS) -5- ((7-chloro-1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate
Figure BDA0002321528230001372
Tert-butylcis-5-aminohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (100mg, 0.442mmol), 5, 7-dichloro-1, 6-naphthyridine (83mg, 0.42mmol) and diisopropylethylamine (0.208mL, 1.26mmol) were dissolved in DMSO (2 mL), heated to 110 ℃ and stirred for 15 hours, the reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure after filtration, and the resulting product was isolated and purified by silica gel column chromatography to give the title compound (142mg, 87%).
MS m/z(ESI):389.4[M+H] + .
The second step is that: preparation of 3- (cis-5- ((7-chloro-1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0002321528230001381
Tert-butylcis-5- ((7-chloro-1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (142mg, 0.365mmol) was dissolved in methanol (2 mL), 4M HCl in 1, 4-dioxane (10 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (10 mL), diisopropylethylamine (1.2 mL, 7.3mmol) and acrylonitrile (0.03mL, 0.438mmol) were sequentially added, the reaction mixture was further stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to give the title compound (123mg, 98%).
MS m/z(ESI):342.1[M+H] + .
The third step: preparation of 3- (cis-5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0002321528230001382
3- (cis-5- ((7-chloro-1, 6-naphthyridin-5-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile (50mg, 0.146mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylic acid ester (44mg, 0.219mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (7mg, 0.009mmol) and cesium carbonate (86mg, 0.263mmol) were added to an ultradry 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen gas, then the vial was heated to 100 ℃ and stirred for 17 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Redissolved in 4M HCl in 1, 4-dioxane (10 mL), stirred at room temperature for 30 min, the solvent concentrated under reduced pressure, and the residue isolated by prep-HPLC to give the title compound (2.6 mg, 4%).
1 H NMR(400MHz,CD 3 OD)δ8.54(dd,J＝9.0,5.7Hz,1H),8.43-8.24(m,1H),7.06(d,J＝5.8Hz,1H),6.66(d,J＝5.2Hz,1H),6.12(s,1H),4.63-4.48(m,1H),3.06-2.56(m,8H),2.55-2.34(m,4H),2.28(s,3H),1.57(s,2H).
MS m/z(ESI):403.2[M+H] + .
Example 6
3- ((3-exo) -3- ((7- ((1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001391
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.146mmol), tert-butyl 3- (l 2-aminoalkyl) -1H-pyrazole-1-carboxylate (40mg, 0.219mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (7mg, 0.009mmol) and cesium carbonate (86mg, 0.263mmol) were added to super-dried 1, 4-dioxane (5 mL), the reaction mixture was deoxygenated by saturation with dry nitrogen gas, then the reaction mixture was heated to 110 ℃ with a sealed tube, stirred for 16 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Redissolved in dichloromethane (2 mL), added trifluoroacetic acid (1 mL), stirred at room temperature for 30 min, concentrated under reduced pressure, and the residue isolated by prep-HPLC to give the title compound (17mg, 31%).
1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),8.81(s,1H),8.58(d,J＝3.3Hz,1H),8.42(d,J＝8.6Hz,1H),7.58(s,1H),7.14(dd,J＝6.2,2.8Hz,1H),6.97(dd,J＝7.9,4.2Hz,1H),6.75(s,1H),6.34(s,1H),4.59-4.42(m,1H),3.33(s,2H),2.63(s,4H),1.97-1.86(m,2H),1.78(ddt,J＝24.7,23.4,7.2Hz,6H).
MS m/z(ESI):389.2[M+H] + .
Example 7
3- ((3-exo) -3- ((7- ((5- (difluoromethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001401
Preparation of 3- ((3-exo) -3- ((7- ((5- (difluoromethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 1.
MS m/z(ESI):439.2[M+H] + .
Example 8
3- ((3-exo) -3- ((7- ((5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001402
Preparation of 3- ((3-exo) -3- ((7- ((5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 1.
MS m/z(ESI):457.2[M+H] + .
Example 9
3- ((3-exo) -3- ((7- ((5-fluoro-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001403
Preparation of 3- ((3-exo) -3- ((7- ((5-fluoro-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 1.
1 H NMR(400MHz,DMSO-d6)δ11.61(d,J＝1.5Hz,1H),9.35(s,1H),8.65(dd,J＝4.3,1.2Hz,1H),8.49(d,J＝8.8Hz,1H),7.40(d,J＝7.8Hz,1H),7.07(dd,J＝8.4,4.3Hz,1H),6.25(s,1H),5.77(dd,J＝6.0,2.1Hz,1H),4.47-4.39(m,1H),3.32(s,2H),2.62(t,J＝4.2Hz,4H),1.95-1.86(m,2H),1.83-1.70(m,6H).
MS m/z(ESI):407.2[M+H] + .
Example 10
3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -1H-pyrazole-5-carbonitrile
Figure BDA0002321528230001411
Preparation of 3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -1H-pyrazole-5-carbonitrile refers to example 1.
MS m/z(ESI):414.2[M+H] + .
Example 11
3- ((3-exo) -3- ((7- ((5-ethyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001412
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (100mg, 0.292mmol), 5-ethyl-1H-pyrazol-3-amine (65mg, 0.584mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (115mg, 0.146mmol) and carbonic acid (286mg, 0.87mmol) were added to an ultradry 1, 4-epoxyhexacyclic compound (10 mL), and the reaction solution was saturated with dry nitrogen and heated to 150 ℃ with a microwave synthesizer for 8 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the title compound (2.2mg, 2%) was obtained by separation sequentially through silica gel column chromatography and reverse phase HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),8.71(s,1H),8.57(dd,J＝4.1,1.4Hz,1H),8.40(d,J＝7.1Hz,1H),7.12(d,J＝8.4Hz,1H),6.95(dd,J＝8.1,4.4Hz,1H),6.68(s,1H),6.16(s,1H),4.53(dd,J＝12.8,5.6Hz,1H),3.33(s,2H),2.63(ddd,J＝24.2,9.2,4.8Hz,6H),1.92(dd,J＝8.1,4.4Hz,2H),1.85-1.66(m,6H),1.20(t,J＝7.6Hz,3H).
MS m/z(ESI):417.2[M+H] + .
Example 12
3- ((3-exo) -3- ((7- ((5-cyclopropyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001421
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (100mg, 0.292mmol), 5-cyclopropyl-1H-pyrazol-3-amine (72mg, 0.585mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (115mg, 0.146mmol) and cesium carbonate (285mg, 0.87mmol) were added to super-dried 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen and heated to 150 ℃ with microwaves with stirring for 3 hours, then cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography and reverse phase HPLC to give the title compound (20mg, 16%).
1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.67(s,1H),8.57(d,J＝3.2Hz,1H),8.44-8.36(m,1H),7.12(ddd,J＝12.4,9.6,3.9Hz,1H),6.96(dd,J＝8.0,3.9Hz,1H),6.70(s,1H),6.06(s,1H),4.53(d,J＝4.9Hz,1H),3.33(s,2H),2.63(s,4H),2.01-1.63(m,9H),0.91(d,J＝7.5Hz,2H),0.70(d,J＝4.3Hz,2H).
MS m/z(ESI):429.2[M+H] + .
Example 13
3- ((3-exo) -3- ((7- ((5- (oxetan-3-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001431
Preparation of 3- ((3-exo) -3- ((7- ((5- (oxetan-3-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 12.
MS m/z(ESI):445.2[M+H] + .
Example 14
3- ((3-exo) -3- ((7- ((5- (1-methylazetidin-3-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001432
Preparation of 3- ((3-exo) -3- ((7- ((5- (1-methylazetidin-3-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 12.
MS m/z(ESI):458.3[M+H] + .
Example 15
3- ((3-exo) -3- ((7- ((4, 5-dimethyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001433
Preparation of 3- ((3-exo) -3- ((7- ((4, 5-dimethyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 12.
1 H NMR(400MHz,DMSO-d6)δ8.76(dd,J＝4.2,1.3Hz,1H),8.60(d,J＝8.2Hz,1H),7.44(d,J＝8.4Hz,1H),7.24(dd,J＝8.3,4.4Hz,1H),7.10(s,1H),4.97(s,2H),4.52(dd,J＝16.9,8.1Hz,1H),3.33(s,2H),2.66(dd,J＝10.4,2.9Hz,7H),1.92(ddd,J＝5.9,3.4,1.8Hz,2H),1.85(s,3H),1.72(ddd,J＝20.9,11.4,4.3Hz,6H).
MS m/z(ESI):417.1[M+H] + .
Example 16
3- ((3-exo) -3- ((7- ((4-fluoro-5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001441
Preparation of 3- ((3-exo) -3- ((7- ((4-fluoro-5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 12.
MS m/z(ESI):421.2[M+H] + .
Example 17
3- ((3-exo) -3- ((7- ((5-methoxy-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001442
Preparation of 3- ((3-exo) -3- ((7- ((5-methoxy-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 12.
MS m/z(ESI):419.2[M+H] + .
Example 18
3- ((3-exo) -3- ((7- ((5- (methoxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001451
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (72mg, 0.21mmol), 2- (2-aminothiazol-5-yl) propan-2-ol (54mg, 0.42mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (83mg, 0.105mmol) and carbonic acid (205mg, 0.63mmol) were added to an ultradry 1, 4-epoxyhexacyclic compound (10 mL), and the reaction mixture was saturated with dry nitrogen and heated to 150 ℃ with a microwave synthesizer and stirred for 7 hours. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure and isolated by prep-HPLC to give the title compound (22.4 mg, 25%).
1 H NMR(400MHz,DMSO-d 6 )δ8.57(d,J＝3.5Hz,1H),8.50(d,J＝8.6Hz,1H),7.07(dd,J＝8.0,4.7Hz,1H),6.74(s,1H),6.35(s,1H),4.63(td,J＝10.8,6.1Hz,1H),4.43(s,2H),3.71-3.48(m,2H),3.35(s,3H),2.93(s,2H),2.75(s,2H),2.23-1.75(m,8H).
MS m/z(ESI):433.2[M+H] + .
Example 19
3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001452
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (100mg, 0.292mmol), (3-amino-1H-pyrazol-5-yl) methanol (66mg, 0.584mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (115mg, 0.146mmol) and carbonic acid (286mg, 0.877mmol) were added to an ultradry 1, 4-epoxyhexacyclic compound (15 mL), the reaction mixture was saturated with dry nitrogen and heated to 150 ℃ with a microwave synthesizer and the reaction was stirred for 6 hours. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, and separated by prep-HPLC to give the title compound (15.7 mg, 13%).
1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),8.77(s,1H),8.58(d,J＝3.3Hz,1H),8.41(d,J＝8.1Hz,1H),7.13(s,1H),6.97(dd,J＝7.9,4.4Hz,1H),6.72(s,1H),6.24(s,1H),5.20(d,J＝1.8Hz,1H),4.53(dd,J＝6.8,4.2Hz,1H),4.45(d,J＝5.2Hz,2H),3.33(s,2H),2.63(s,4H),1.95-1.87(m,2H),1.80(dd,J＝13.3,7.7Hz,4H),1.75-1.67(m,2H).
MS m/z(ESI):419.2[M+H] + .
Example 20
3- ((3-exo) -3- ((7- ((5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001461
Preparation of 3- ((3-exo) -3- ((7- ((5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 2.
MS m/z(ESI):447.3[M+H] + .
Example 21
3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -1H-pyrazole-5-carboxamide
Figure BDA0002321528230001462
Preparation of 3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -1H-pyrazole-5-carboxamide reference example 2.
MS m/z(ESI):432.2[M+H] + .
Example 22
3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -N-methyl-1H-pyrazole-5-carboxamide
Figure BDA0002321528230001471
Preparation of 3- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -N-methyl-1H-pyrazole-5-carboxamide reference example 2.
MS m/z(ESI):446.2[M+H] + .
Example 23
3- ((3-exo) -3- ((7- ((2-methyl-1H-imidazol-4-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001472
Preparation of 3- ((3-exo) -3- ((7- ((2-methyl-1H-imidazol-4-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 6.
MS m/z(ESI):403.2[M+H] + .
Example 24
3- ((3-exo) -3- ((7- ((5-methyl-1H-1, 2, 4-triazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001481
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (100mg, 0.292mmol), 5-methyl-4H-1, 2, 4-triazole-3-amine hydrochloride (47.2mg, 0.351mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (115mg, 0.146mmol) and carbonic acid (171mg, 0.526mmol) were added to ultradry 1, 4-epoxyhexacyclic (10 mL), and the reaction solution was saturated with dry nitrogen and heated to 150 ℃ with a microwave synthesizer and stirred for 4 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the title compound (12.4 mg, 10.5%) was obtained by separation sequentially through silica gel column chromatography and reverse phase HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ12.73(s,1H),9.19(s,1H),8.68-8.62(m,1H),8.47(d,J＝8.3Hz,1H),7.23(dt,J＝39.0,8.1Hz,2H),7.08(dd,J＝8.2,4.2Hz,1H),4.48(td,J＝12.0,6.7Hz,1H),3.31-3.30(m,2H),2.63(t,J＝3.0Hz,4H),2.28(s,3H),1.92-1.80(m,6H),1.69(t,J＝11.8Hz,2H).
MS m/z(ESI):404.2[M+H] + .
Example 25
3- ((3-exo) -3- ((7- ((1-methyl-1H-imidazol-4-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001482
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (100mg, 0.292mmol), 1-methyl-1H-imidazol-4-amine hydrochloride (78mg, 0.585mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (115mg, 0.146mmol) and cesium carbonate (1.46mmol) were added to ultradry 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen and heated to 140 ℃ with microwaves with stirring for 4 hours, then cooled to room temperature, the filtrate was concentrated under reduced pressure after filtration, and the title compound (4.4mg, 4%) was purified by silica gel column chromatography and reverse phase HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H),8.55(dd,J＝4.2,1.3Hz,1H),8.40(d,J＝8.4Hz,1H),7.36(s,1H),7.17(d,J＝7.5Hz,2H),6.92(dd,J＝8.3,4.3Hz,1H),6.32(s,1H),4.56(ddd,J＝17.5,12.0,6.1Hz,1H),3.64(s,3H),3.34(s,2H),2.64(s,4H),2.06-1.65(m,8H).
MS m/z(ESI):403.2[M+H] + .
Example 26
3- ((3-exo) -3- ((7- ((1-methyl-1H-1, 2, 4-triazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001491
Preparation of 3- ((3-exo) -3- ((7- ((1-methyl-1H-1, 2, 4-triazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 25.
MS m/z(ESI):404.2[M+H] + .
Example 27
3- ((3-exo) -3- ((7- ((1H-indazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001492
Preparation of 3- ((3-exo) -3- ((7- ((1H-indazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 6.
MS m/z(ESI):439.2[M+H] + .
Example 28
3- ((3-exo) -3- ((7- ((1H-pyrazolo [3,4-c ] pyridin-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001501
Preparation of 3- ((3-exo) -3- ((7- ((1H-pyrazolo [3,4-c ] pyridin-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 6.
MS m/z(ESI):440.2[M+H] + .
Example 29
3- ((3-exo) -3- ((7- (pyrazin-2-ylamino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001502
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.146mmol), pyrazin-2-amine (21mg, 0.219mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (7mg, 0.009mmol) and cesium carbonate (86mg, 0.263mmol) were added to extra dry 1, 4-dioxane (5 mL), the reaction mixture was saturated with dry nitrogen and then sealed and heated to 110 ℃ with stirring for 23 hours, then cooled to room temperature, filtered, concentrated under reduced pressure, and isolated by prep-HPLC to give the title compound (30.2mg, 52%).
1 H NMR(400MHz,DMSO-d 6 )δ9.65(s,1H),9.28(d,J＝0.4Hz,1H),8.70(d,J＝3.1Hz,1H),8.55(d,J＝8.3Hz,1H),8.33-8.20(m,3H),8.07(d,J＝2.5Hz,1H),7.40(d,J＝8.0Hz,1H),7.15(dd,J＝8.3,4.3Hz,1H),7.04(s,1H),4.54(ddd,J＝16.1,11.1,6.6Hz,1H),3.34(d,J＝0.9Hz,2H),2.64(s,4H),2.00-1.69(m,8H).
MS m/z(ESI):401.3[M+H] + .
Example 30
3- ((3-exo) -3- ((7- (pyrimidin-2-ylamino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001511
Preparation of 3- ((3-exo) -3- ((7- (pyrimidin-2-ylamino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 29.
MS m/z(ESI):401.2[M+H] + .
Example 31
3- ((3-exo) -3- ((7- ((5- (2-hydroxypropan-2-yl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001512
The first step is as follows: preparation of 2- (2-aminothiazol-5-yl) propan-2-ol
Figure BDA0002321528230001513
Dissolving ethyl 2-aminothiazole-5-carboxylic acid ester (345mg, 2.0 mmol) in dry tetrahydrofuran (10 mL), cooling to 0 ℃, dropwise adding magnesium methylbromide (3M diethyl ether solution, 4mL, 12mmol) into the reaction liquid under the protection of nitrogen, and continuously stirring the reaction liquid at 0 ℃ for reacting for 17 hours. After the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (237mg, 75%).
MS m/z(ESI):159.2[M+H] + .
The second step of reaction: preparation of 3- ((3-exo) -3- ((7- ((5- (2-hydroxypropan-2-yl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001521
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.146mmol), 2- (2-aminothiazol-5-yl) propan-2-ol (46mg, 0.292mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (57mg, 0.3mmol) and Cbz (07mg, 0.438mmol) were added to ultradry 1, 4-epoxyhexacyclic (5 mL), and the reaction mixture was saturated with dry nitrogen and heated to 90 ℃ with stirring for 4 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the title compound (29.8mg, 44%) was isolated by prep-HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),8.67(dd,J＝4.2,1.2Hz,1H),8.56(d,J＝8.3Hz,1H),7.40(d,J＝8.5Hz,1H),7.13-7.07(m,2H),6.49(s,1H),5.25(s,1H),4.83(dd,J＝17.2,8.5Hz,1H),3.35(s,2H),2.65(s,4H),1.93(dt,J＝12.9,9.8Hz,4H),1.80(dd,J＝8.5,1.5Hz,4H),1.52(s,6H).
MS m/z(ESI):464.2[M+H] + .
Example 32
3- ((3-exo) -3- ((7- ((5- (1-hydroxycyclopropyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001522
Preparation of 3- ((3-exo) -3- ((7- ((5- (1-hydroxycyclopropyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 31.
MS m/z(ESI):462.2[M+H] + .
Example 33
3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) -4-methylthiooxazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001531
Preparation of 3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) -4-methylthiooxazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 31.
MS m/z(ESI):450.2[M+H] + .
Example 34
2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-sulfonamide
Figure BDA0002321528230001532
Preparation of 2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-sulfonamide refers to example 2.
MS m/z(ESI):485.1[M+H] + .
Example 35
2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-carboxamide
Figure BDA0002321528230001541
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((7- ((5-carbamoylthiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001542
Tert-butyl (3-exo) -3- ((7- ((5-cyanothiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (72mg, 0.15mmol) was dissolved in DMSO (5 mL), and lithium hydroxide monohydrate (19mg, 0.45mmol) and 30% aqueous hydrogen peroxide (0.18mL, 0.45mmol) were added successively with stirring at room temperature, and stirring was continued at room temperature for 21 hours. The reaction solution was diluted with ethyl acetate, the organic phase was washed with supersaturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the crude product was used directly in the next reaction.
MS m/z(ESI):496.1[M+H] + .
The second step of reaction: preparation of 2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-carboxamide
Figure BDA0002321528230001543
Tert-butyl (3-exo) -3- ((7- ((5-carbamoylthiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was dissolved in 4M HCl 1.4-dioxane (10 mL) and the reaction was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (10 mL), DIPEA (0.74mL, 4.5 mmol) and acrylonitrile (0.2mL, 3.0 mmol) were added in this order, and the reaction mixture was stirred at room temperature for 70 minutes. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (6.1mg, 9%).
1 H NMR(400MHz,DMSO-d 6 )δ11.23(s,1H),8.71(dd,J＝4.2,1.3Hz,1H),8.61(d,J＝7.9Hz,1H),7.95(s,1H),7.70(s,1H),7.49(d,J＝8.6Hz,1H),7.16(dd,J＝8.4,4.3Hz,1H),7.10(s,1H),6.55(s,1H),4.82(dd,J＝17.6,9.3Hz,1H),3.32-3.27(m,2H),2.65(t,J＝3.1Hz,4H),2.00(dd,J＝14.0,6.3Hz,2H),1.91-1.74(m,6H).
Example 36
6- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) pyridazine-3-carboxamide
Figure BDA0002321528230001551
Preparation of 6- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) pyridazine-3-carboxamide reference example 2.
MS m/z(ESI):444.2[M+H] + .
Example 37
6- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -N-methylpyridazine-3-carboxamide
Figure BDA0002321528230001552
Preparation of 6- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -N-methylpyridazine-3-carboxamide reference example 2.
MS m/z(ESI):458.2[M+H] + .
Example 38
5- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) pyrazine-2-carboxamide
Figure BDA0002321528230001561
Preparation of 5- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) pyrazine-2-carboxamide reference example 2.
MS m/z(ESI):444.2[M+H] + .
Example 39
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001562
The first step is as follows: preparation of tert-butyl- (3-exo) -3- ((2-chloro-7-tosyl-7 h-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001563
To a solution of 2, 4-dichloro-7-toluenesulfonyl-7-hydro-pyrrolo [2,3-d ] pyrimidine (171mg, 0.5 mmol) in ethanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (136mg, 0.6 mmol) and DIPEA (129mg, 1mmol) in this order, followed by stirring at 80 ℃ under reflux for 1 hour. After completion of the reaction, the reaction mixture was extracted with dichloromethane (15mL. Times.3), washed with a saturated aqueous solution of sodium chloride (15mL. Times.3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a white solid (250mg, 94%).
MS m/z(ESI):532.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7 hydro-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001571
Tert-butyl- (3-exo) -3- ((2-chloro-7-tosyl-7 h-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (20mg, 0.47mmol), tert-butyl-3 amino-5-methyl-1 h-pyrazole-1-carboxylic acid (111mg, 0.56mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (37mg, 0.047mmol) and cesium carbonate (306mg, 0.94mmol) were suspended in a solution of ultra-dried 1, 4-epoxyhexacyclic compound (10 mL), replaced with nitrogen three times and then stirred at 140 ℃ for 4 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a yellow solid (100mg, 48%).
MS m/z(ESI):439.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7 hydro-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001572
Tert-butyl- (3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -7 hydro-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.23mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; methanol (10 mL) was then added to dissolve it, DIPEA (118mg, 0.91mmol) was added slowly dropwise, stirring was continued at room temperature for 10 minutes, and acrylonitrile (18mg, 0.35mmol) was added followed by 2 hours of stirring. The reaction was concentrated under reduced pressure and the resulting product was subjected to prep-HPLC to give the title compound as a yellow solid (15.4 mg, 17%).
1 H NMR(400MHz,DMSO)δ11.58(s,1H),10.95(s,1H),8.70(s,1H),7.04(s,1H),6.72(s,1H),6.39(s,1H),6.32-6.17(m,1H),4.46(s,1H),3.30(s,2H),2.62(dd,J＝7.2,4.0Hz,4H),2.17(s,3H),1.97-1.89(m,2H),1.84-1.59(m,6H).
MS m/z(ESI):392.2[M+H] + .
Example 40
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001581
The first step is as follows: preparation of 2, 4-dichloro-5- ((2-nitrophenyl) sulfonyl) -5-hydro-pyrrolo [3,2-d ] pyrimidine
Figure BDA0002321528230001582
To a solution of 2, 4-dichloro-5-hydro-pyrrolo [3,2-D ] pyrimidine (470mg, 2.5mmol) and o-nitrobenzenesulfonyl chloride (600mg, 2.75mmol) in tetrahydrofuran (20 mL) was slowly added sodium hydride (120mg, 5mmol) under ice-water bath conditions, followed by slowly warming to room temperature and stirring for 1 hour. After completion of the reaction, the reaction was quenched by dropwise addition of water (150 mL) under ice-water bath conditions, and after stirring at room temperature for 1 hour, the title compound was obtained as a pale yellow solid (800mg, 86%) by filtration.
MS m/z(ESI):372.9[M+H] + .
The second step: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) -5- ((2-nitrophenyl) sulfonyl) -5-hydro-pyrrolo [3,2-d ] pyrimidin-4-amine
Figure BDA0002321528230001591
To a solution of 2, 4-dichloro-5- ((2-nitrophenyl) sulfonyl) -5 hydro-pyrrolo [3,2-d ] pyrimidine (800mg, 2.15mmol) in ethanol (20 mL) was added 3-amino-5-methylpyrazole (250mg, 2.58mmol), DIPEA (555mg, 4.3mmol) in that order, followed by stirring at 80 ℃ for 2 hours under reflux. After completion of the reaction, a solid precipitated in the reaction solution, and after filtration, the filter cake was washed with ethanol (15mL × 3), and the filter cake was dried to obtain the title compound as a yellowish brown solid (370mg, 40%).
MS m/z(ESI):434.0[M+H] + .
The third step: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -5 hydro-pyrrolo [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001592
To a solution of 2-chloro-N- (5-methyl-1 h-pyrazol-3-yl) -5- ((2-nitrophenyl) sulfonyl) -5 h-pyrrolo [3,2-d ] pyrimidin-4-amine (370mg, 0.85mmol) in N-butanol (5 mL) was added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (233mg, 1.03mmol), DIPEA (220mg, 1.71mmol) in this order, followed by stirring under microwave conditions at 160 ℃ for 10 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale yellow solid (40mg, 11%).
MS m/z(ESI):593.1[M+H] + .
The fourth step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -5 hydro-pyrrolo [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001601
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -5 hydro-pyrrolo [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (30mg, 0.07mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, methanol (5 mL) was added to dissolve it, DIPEA (35mg, 0.28mmol) was added slowly dropwise, and stirring was continued for 10 minutes at room temperature, followed by addition of acrylonitrile (5mg, 0.1mmol) and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a pale yellow solid (8.2mg, 31%).
1 H NMR(400MHz,DMSO)δ11.93(s,1H),10.57(s,1H),9.43(s,1H),7.29(s,1H),6.77(s,1H),6.02(s,1H),5.77(s,1H),4.12(s,1H),3.28(s,2H),2.62(s,4H),2.22(s,3H),1.90(s,2H),1.81-1.43(m,6H).
MS m/z(ESI):392.2[M+H] + .
Example 41
3- ((3-exo) -3- ((5-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001602
Preparation of 3- ((3-exo) -3- ((5-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):406.2[M+H] + .
Example 42
3- ((3-exo) -3- ((5-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001611
Preparation of 3- ((3-exo) -3- ((5-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):406.2[M+H] + .
Example 43
3- ((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001612
Preparation of 3- ((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):406.2[M+H] + .
Example 44
3- ((3-exo) -3- ((6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001621
Preparation of 3- ((3-exo) -3- ((6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):406.2[M+H] + .
Example 45
2- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonitrile
Figure BDA0002321528230001622
Preparation of 2- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonitrile reference example 3.
MS m/z(ESI):417.2[M+H] + .
Example 46
3- ((3-exo) -3- ((5-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001623
Preparation of 3- ((3-exo) -3- ((5-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):410.2[M+H] + .
Example 47
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001631
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):393.2[M+H] + .
Example 48
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001632
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):393.2[M+H] + .
Example 49
3- ((3-exo) -3- ((8-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001641
Preparation of 3- ((3-exo) -3- ((8-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):407.2[M+H] + .
Example 50
3- ((3-exo) -3- ((3-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001642
Preparation of 3- ((3-exo) -3- ((3-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 39.
MS m/z(ESI):407.2[M+H] + .
Example 51
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001643
The first step is as follows: preparation of 4, 6-dichloro-1- (tetrahydro-2-hydro-pyran-2-yl) -1-hydro-pyrazolo [3,4-d ] pyrimidine
Figure BDA0002321528230001651
To a solution of 4, 6-dichloro-1-hydro-pyrazolo [3,4-d ] pyrimidine (200mg, 1.06mmol) in tetrahydrofuran (5 mL) was added p-toluenesulfonic acid monohydrate (19mg, 0.1mmol) and 3, 4-dihydro-2-hydro-pyran (133mg, 1.59mmol) in this order, followed by stirring at 60 ℃ under reflux for 2 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous solution of sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a white solid (269mg, 93%).
MS m/z(ESI):273.0[M+H] + .
The second step: preparation of 6-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) -1- (tetrahydro-2 hydro-pyran-2-yl) -1 hydro-pyrazolo [3,4-d ] pyrimidin-4-amine
Figure BDA0002321528230001652
To a solution of 4, 6-dichloro-1- (tetrahydro-2 h-pyran-2-yl) -1 h-pyrazolo [3,4-d ] pyrimidine (250mg, 0.93mmol) in ethanol (10 mL) was added 3-amino-5-methylpyrazole (108mg, 1.12mmol), DIPEA (240mg, 1.86mmol) in this order, followed by stirring at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a white solid (254mg, 82%).
MS m/z(ESI):334.1[M+H] + .
The third step: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) -1- (tetrahydro-2-hydro-pyran-2-yl) -1-hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001653
To a solution of 6-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) -1- (tetrahydro-2 hydro-pyran-2-yl) -1 hydro-pyrazolo [3,4-d ] pyrimidin-4-amine (200mg, 0.6 mmol) in N-butanol (5 mL) was added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (203mg, 0.9 mmol), DIPEA (155mg, 1.2 mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a pale yellow solid (144mg, 46%).
MS m/z(ESI):524.2[M+H] + .
The fourth step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -1 hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001661
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -1- (tetrahydro-2 hydro-pyran-2-yl) -1 hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (144mg, 0.28mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL) of hydrochloric acid, and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, methanol (10 mL) was added to dissolve it, DIPEA (142mg, 1.12mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (22mg, 0.41mmol) was added followed by stirring for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the title compound was obtained as a white solid by prep-HPLC (54.6 mg, 51%).
1 H NMR(400MHz,DMSO-d 6 )δ＝12.49(s,1H),12.03(s,1H),10.02(s,1H),8.05(s,1H),6.81-6.47(m,2H),4.11(s,1H),3.29(s,2H),2.62(s,4H),2.19(s,3H),1.91(s,2H),1.71-1.62(m,6H).
MS m/z(ESI):393.2[M+H] + .
Example 52
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001671
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 39.
MS m/z(ESI):393.2[M+H] + .
Example 53
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001672
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):391.2[M+H] + .
Example 54
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001673
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):391.2[M+H] + .
Example 55
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-c ] pyridin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001681
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-c ] pyridin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 51.
MS m/z(ESI):392.2[M+H] + .
Example 56
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001682
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):392.2[M+H] + .
Example 57
3- ((3-exo) -3- ((7-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001691
Preparation of 3- ((3-exo) -3- ((7-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 40.
MS m/z(ESI):407.2[M+H] + .
Example 58
3- ((3-exo) -3- ((7-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001692
Preparation of 3- ((3-exo) -3- ((7-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-purin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 39.
MS m/z(ESI):407.2[M+H] + .
Example 59
3- ((3-exo) -3- ((9-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001693
Preparation of 3- ((3-exo) -3- ((9-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 40.
MS m/z(ESI):407.2[M+H] + .
Example 60
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001701
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine
Figure BDA0002321528230001702
To a solution of 2, 4-dichlorothieno [3,2-d ] pyrimidine (205mg, 1mmol) in N-methylpyrrolidone (10 mL) were added 3-amino-5-methylpyrazole (116mg, 1.2 mmol) and DIPEA (258mg, 2mmol) in this order, followed by stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50 mL) was added to the reaction solution, and the precipitated solid was filtered and slurried with ethyl acetate to give the title compound as a pale yellow solid (135mg, 51%).
MS m/z(ESI):266.0[M+H] + .
The second step: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001703
To a solution of 2-chloro-N- (5-methyl-1 h-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (135mg, 0.51mmol) in N-butanol (5 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (138mg, 0.61mmol), DIPEA (129mg, 1mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale yellow solid (146mg, 63%).
MS m/z(ESI):456.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001711
Dissolving tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (146mg, 0.32mmol) in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirring at room temperature for 30 minutes, and then concentrating the reaction solution; methanol (10 mL) was then added to dissolve it, DIPEA (166mg, 1.28mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and after addition of acrylonitrile (25mg, 0.48mmol), stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (14.4 mg, 11%).
1 H NMR(400MHz,DMSO)δ12.02(s,1H),9.70(s,1H),7.89(s,1H),6.99(s,1H),6.44(d,J＝59.6Hz,2H),4.14(s,1H),3.29(s,2H),2.62(s,4H),2.22(s,3H),1.89(s,2H),1.64(dd,J＝47.8,17.6Hz,6H).
MS m/z(ESI):409.2[M+H] + .
Example 61
3- ((3-exo) -3- ((7-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001712
Preparation of 3- ((3-exo) -3- ((7-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 60.
MS m/z(ESI):423.2[M+H] + .
Example 62
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001721
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine
Figure BDA0002321528230001722
To a solution of 2, 4-dichlorothieno [2,3-d ] pyrimidine (205mg, 1mmol) in N-methylpyrrolidone (10 mL) were added 3-amino-5-methylpyrazole (116mg, 1.2 mmol) and DIPEA (258mg, 2 mmol) in this order, followed by stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50 mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (250mg, 94%).
MS m/z(ESI):266.0[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001723
To a solution of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (250mg, 0.94mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (256 mg, 1.13mmol), DIPEA (242mg, 1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale yellow solid (200mg, 47%).
MS m/z(ESI):456.1[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001731
Dissolving tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid ester (200mg, 0.44mmol) in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 5 mL), stirring at room temperature for 30 minutes, and then concentrating the reaction solution; then, methanol (10 mL) was added to dissolve it, DIPEA (227mg, 1.76mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (35mg, 0.66mmol) was added followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (31.6 mg, 18%).
1 H NMR(400MHz,DMSO)δ12.13(s,1H),9.93(s,1H),7.73(s,1H),6.88(d,J＝117.2Hz,3H),4.27(s,1H),3.37(s,2H),2.70(s,4H),2.32(s,3H),1.99(s,2H),1.86-1.61(m,6H).
MS m/z(ESI):409.2[M+H] + .
Example 63
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001732
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):409.2[M+H] + .
Example 64
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001741
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 60.
MS m/z(ESI):410.2[M+H] + .
Example 65
3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001742
Preparation of 3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):410.2[M+H] + .
Example 66
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001751
The first step is as follows: preparation of 5-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine
Figure BDA0002321528230001752
To a solution of 5, 7-dichlorothiazolo [5,4-d ] pyrimidine (206mg, 1mmol) in dimethylsulfoxide (10 mL) was added 3-amino-5-methylpyrazole (116mg, 1.2 mmol) and DIPEA (258mg, 2 mmol) in this order, followed by heating and stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50 mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (200mg, 75%).
MS m/z(ESI):267.0[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001753
To a solution of 5-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine (200mg, 0.75mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (204mg, 0.9 mmol), DIPEA (193mg, 1.5 mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a pale yellow solid (74mg, 22%).
MS m/z(ESI):457.1[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001761
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (74mg, 0.16mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; methanol (10 mL) was then added to dissolve it, DIPEA (83mg, 0.64mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (9mg, 0.24mmol) was added followed by stirring for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (16.3mg, 25%).
1 H NMR(400MHz,DMSO)δ12.07(s,1H),9.33(s,1H),8.76(d,J＝20.4Hz,1H),6.96(s,1H),6.55(d,J＝12.0Hz,1H),4.14(s,1H),3.31(s,2H),2.61(s,4H),2.21(s,3H),1.91(s,2H),1.78-1.54(m,6H).
Example 67
3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001762
Preparation of 3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):410.2[M+H] + .
Example 68
3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001771
Preparation of 3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 40.
MS m/z(ESI):392.2[M+H] + .
Example 69
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001772
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 39.
MS m/z(ESI):392.2[M+H] + .
Example 70
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001773
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 39.
MS m/z(ESI):392.2[M+H] + .
Example 71
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001781
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 2.
MS m/z(ESI):425.2[M+H] + .
Example 72
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001782
The first step is as follows: preparation of 3- ((3-exo) -3- ((2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001783
To a solution of 5,7-dichloropyrrolo [2,1-f ] [1,2,4] triazine (188mg, 1mmol) in ethanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (271mg, 1.2 mmol) and DIPEA (258mg, 2mmol) in this order, and the reaction was stirred at 80 ℃ under reflux for 2 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a pale yellow solid (350mg, 93%).
MS m/z(ESI):378.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001791
3- ((3-exo) -3- ((2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (350mg, 0.93mmol), tert-butyl-3 amino-5-methyl-1 h-pyrazole-1-carboxylic acid (219mg, 1.11mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (73mg, 0.093mmol) and potassium phosphate (591mg, 2.79mmol) were suspended in a solution of ultradry 1, 4-epoxyhexacyclic (20 mL), replaced with nitrogen three times, then heated with a 110 ℃ lock tube and stirred, the reaction was completed, the reaction solution was extracted with dichloromethane (15mL x 3), the saturated aqueous sodium chloride solution (1mL), the organic phase was collected, and the organic phase was filtered and the resulting product was purified by silica gel chromatography (95 mg: 24 mg).
MS m/z(ESI):439.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001792
Tert-butyl- (3-exo) -3- ((2- ((5-methyl-1 hydro-pyrazol-3-yl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.23mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, methanol (10 mL) was added to dissolve it, DIPEA (119mg, 0.92mmol) was added slowly dropwise thereto, and the mixture was stirred at room temperature for 10 minutes, followed by addition of acrylonitrile (18mg, 0.35mmol) and further stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (31.8mg, 35%).
1 H NMR(400MHz,DMSO)δ11.67(s,1H),8.48(s,1H),7.74(s,1H),7.35(s,1H),6.73(s,1H),6.36(s,2H),4.49(s,1H),3.30(s,2H),2.72-2.59(m,4H),2.18(s,3H),1.91(s,2H),1.83-1.64(m,6H).
MS m/z(ESI):392.2[M+H] + .
Example 73
3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001801
Preparation of 3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 6.
MS m/z(ESI):393.2[M+H] + .
Example 74
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001802
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 72.
MS m/z(ESI):393.2[M+H] + .
Example 75
3- ((3-exo) -3- ((2-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001811
Preparation of 3- ((3-exo) -3- ((2-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 72.
MS m/z(ESI):407.2[M+H] + .
Example 76
3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001812
Preparation of 3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 66.
MS m/z(ESI):393.2[M+H] + .
Example 77
3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001813
Preparation of 3- ((3-exo) -3- ((6- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 72.
MS m/z(ESI):393.2[M+H] + .
Example 78
3- ((3-exo) -3- ((5- ((5- (hydroxymethyl) thiazol-2-yl) amino) imidazo [1,2-c ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001821
Preparation of 3- ((3-exo) -3- ((5- ((5- (hydroxymethyl) thiazol-2-yl) imidazo [1,2-c ] pyrimidin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 2.
MS m/z(ESI):425.2[M+H] + .
Example 79
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001822
The first step is as follows: preparation of 3- ((3-exo) -3- ((7-chloroimidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001823
To a solution of 5, 7-dichloroimidazo [1,2-c ] pyrimidine (188mg, 1mmol) in ethanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (271mg, 1.2 mmol), DIPEA (258mg, 2mmol) in that order, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 99) to obtain the title compound as a pale yellow solid (374mg, 99%).
MS m/z(ESI):378.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001831
33- ((3-exo) -3- ((7-chloroimidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (330mg, 0.87mmol), tert-butyl-3 amino-5-methyl-1 h-pyrazole-1-carboxylic acid (259mg, 1.31mmol), methanesulfonic acid (2-dicyclohexylphosphine-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (82mg, 0.09mmol) and sodium tert-butoxide (252mg, 2.2 mmol) were suspended in a solution of ultradry 1, 4-epoxyhexacyclic (20 mL), replaced with nitrogen three times, followed by microwave reaction at 130 ℃ for 4 hours, the reaction was terminated, the reaction solution was extracted with dichloromethane (15mL x 3), the saturated aqueous sodium chloride solution was washed (1mL), the organic phase was collected, filtered over 6220 mL of silica gel, and the resulting product was purified by silica gel chromatography (95 mg: 5 mg).
MS m/z(ESI):439.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001832
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (30mg, 0.07mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, methanol (5 mL) was added to dissolve it, DIPEA (36mg, 0.28mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes, followed by addition of acrylonitrile (5mg, 0.1mmol) and further stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a yellow solid (8.9 mg, 32%).
1 H NMR(400MHz,DMSO)δ＝11.73(s,1H),8.65(s,1H),7.71(s,1H),7.23(d,J＝8.4,1H),7.19(d,J＝1.2,1H),6.55(s,1H),5.99(s,1H),4.48-4.21(m,1H),3.30(s,2H),2.62(m,4H),2.20(s,3H),1.97-1.90(m,2H),1.87-1.79(m,2H),1.76-1.56(m,4H).
MS m/z(ESI):392.2[M+H] + .
Example 80
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazolo [1,5-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001841
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazolo [1,5-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 66.
MS m/z(ESI):392.2[M+H] + .
Example 81
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001842
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 79.
MS m/z(ESI):393.2[M+H] + .
Example 82
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001851
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 79.
MS m/z(ESI):393.2[M+H] + .
Example 83
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-b ] pyridazin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001852
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-b ] pyridazin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 6.
MS m/z(ESI):392.2[M+H] + .
Example 84
3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-a ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001853
Preparation of 3- ((3-exo) -3- ((8- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-a ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 66.
MS m/z(ESI):392.2[M+H] + .
Example 85
3- ((3-exo) -3- ((1- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-a ] pyrazin-3-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001861
Preparation of 3- ((3-exo) -3- ((1- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,5-a ] pyrazin-3-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 66.
MS m/z(ESI):392.2[M+H] + .
Example 86
3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001862
Preparation of 3- ((3-exo) -3- ((5- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 4.
MS m/z(ESI):403.2[M+H] + .
Example 87
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001871
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
1 H NMR(400MHz,DMSO)δ＝11.76(s,1H),8.90(s,1H),8.08(d,J＝8.0,1H),7.72(s,1H),7.53(t,J＝7.4,1H),7.36(s,1H),7.10(s,1H),6.55(s,1H),4.72-4.58(m,1H),3.30(s,2H),2.64(s,4H),2.20(s,3H),1.92(s,2H),1.86-1.62(m,6H).
MS m/z(ESI):403.2[M+H] + .
Example 88
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001872
The first step is as follows: preparation of 3- ((3-exo) -3- ((7-chloropyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001873
To a solution of 5,7-dichloropyrido [3,4-b ] pyrazine (200mg, 1mmol) in tetrahydrofuran (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (271mg, 1.2 mmol), DIPEA (258mg, 2mmol) in that order, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 99) to obtain the title compound as a pale yellow solid (350mg, 90%).
MS m/z(ESI):390.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) pyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001881
3- ((3-exo) -3- ((7-chloropyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (350mg, 0.9 mmol), tert-butyl-3 amino-5-methyl-1 h-pyrazole-1-carboxylic acid (266mg, 1.35mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (71mg, 0.09mmol) and cesium carbonate (880mg, 2.7 mmol) were suspended in a solution of ultra-dry 1, 4-epoxyhexacyclic compound (20 mL), replaced three times with nitrogen, then the reaction was heated with a 130 ℃ lock tube, the reaction solution was extracted with dichloromethane (5ml x 3), the saturated aqueous sodium chloride solution (1ml x 3) was washed, the organic phase was dried, and then the organic phase was filtered and the resulting product was purified by silica gel chromatography (title compound: 132 mg: 8.8 mg).
MS m/z(ESI):451.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) pyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001882
3- ((3-exo) -3- ((7-chloropyrido [3,4-b ] pyrazin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (32.4mg, 0.07mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 2mL), the reaction mixture was concentrated after stirring at room temperature for 30 minutes, then methanol (5 mL) was added to dissolve it, DIPEA (36mg, 0.28mmol) was slowly added dropwise, stirring was carried out at room temperature for 10 minutes, acrylonitrile (5mg, 0.1mmol) was added followed by stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a yellow solid (8.2mg, 29%).
1 H NMR(400MHz,DMSO)δ＝11.80(s,1H),9.16(s,1H),8.71(d,J＝2.0,1H),8.31(d,J＝1.6,1H),7.48(d,J＝8.4,1H),6.69(s,1H),6.29(s,1H),4.66-4.51(m,1H),3.30(s,2H),2.76(dt,J＝12.4,6.8,4H),2.30(s,3H),2.08-1.93(m,2H),1.85-1.83(m,6H).
MS m/z(ESI):404.2[M+H] + .
Example 89
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001891
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) pyrido [2,3-d ] pyrimidin-4-amine
Figure BDA0002321528230001892
2, 4-dichloropyrido [2,3-d ] pyrimidine (200mg, 1.0mmol), 5-methyl-1H-pyrazol-3-amine (107mg, 1.1mmol) and DIPEA (0.5mL, 3.0mmol) were added to anhydrous ethanol (5 mL), and the mixture was stirred at room temperature for 13.5 hours. Concentrated under reduced pressure, the residual solid was washed with water-ethanol (v \ v =9, 1,20ml), and the filter residue was dried under reduced pressure to give the title compound (185mg, 71%).
MS m/z(ESI):261.1[M+H] + .
The second step is that: preparation of tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001901
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) pyrido [2,3-d ] pyrimidin-4-amine (50mg, 0.192mmol) and tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (87mg, 0.383mmol) were added to N-butanol (3 mL), and heated to 150 ℃ with a microwave synthesizer for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase column chromatography to give the title compound (39.5mg, 46%).
MS m/z(ESI):451.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001902
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (39.5mg, 0.088mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (10 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous methanol (10 mL), DIPEA (0.72mL, 4.38mmol) and acrylonitrile (0.29mL, 4.38mmol) were added in this order, and the reaction mixture was stirred at room temperature for further 75 minutes. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase HPLC to give the title compound (10.6 mg, 30%).
1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),10.11(s,1H),8.71(dd,J＝9.4,1.8Hz,1H),8.63(dd,J＝3.7,1.1Hz,1H),7.02(ddd,J＝11.4,10.6,6.7Hz,2H),6.76(d,J＝84.4Hz,1H),4.26(s,1H),3.31-3.25(m,2H),2.64(t,J＝11.0Hz,4H),2.25(d,J＝13.7Hz,3H),1.92(d,J＝8.5Hz,2H),1.64(dt,J＝25.4,10.4Hz,6H).
MS m/z(ESI):404.3[M+H] + .
Example 90
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001911
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 6.
1 H NMR(400MHz,DMSO)δ＝11.83(s,1H),9.19(s,1H),8.67(s,1H),8.48(s,1H),7.93(s,1H),7.09(s,1H),6.54(s,1H),4.58(s,1H),3.30(s,2H),2.68-2.59(m,4H),2.22(s,3H),1.93(s,2H),1.86-1.67(m,6H).
MS m/z(ESI):404.2[M+H] + .
Example 91
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [4,3-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001912
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [4,3-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):404.2[M+H] + .
Example 92
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) pteridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001921
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) pteridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):405.2[M+H] + .
Example 93
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-1, 2-dihydro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001922
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-1, 2-dihydro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):419.2[M+H] + .
Example 94
3- ((3-exo) -3- ((1-methyl-7- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-1, 2-dihydro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001923
Preparation of 3- ((3-exo) -3- ((1-methyl-7- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-1, 2-dihydro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):433.2[M+H] + .
Example 95
3- ((3-exo) -3- ((6-methyl-3- ((5-methyl-1H-pyrazol-3-yl) amino) -5-carbonyl-5, 6-dihydro-2, 6-naphthyridin-1-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001931
Preparation of 3- ((3-exo) -3- ((6-methyl-3- ((5-methyl-1H-pyrazol-3-yl) amino) -5-carbonyl-5, 6-dihydro-2, 6-naphthyridin-1-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):433.2[M+H] + .
Example 96
5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-2-carbonitrile
Figure BDA0002321528230001932
Preparation of 5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-2-carbonitrile refers to example 88.
MS m/z(ESI):428.2[M+H] + .
Example 97
3- ((3-exo) -3- ((3-fluoro-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001941
Preparation of 3- ((3-exo) -3- ((3-fluoro-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 88.
MS m/z(ESI):421.2[M+H] + .
Example 98
3- ((3-exo) -3- ((4-hydroxy-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001942
Preparation of 3- ((3-exo) -3- ((4-hydroxy-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 88.
MS m/z(ESI):419.2[M+H] + .
Example 99
3- ((3-exo) -3- ((8-methyl-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001943
Preparation of 3- ((3-exo) -3- ((8-methyl-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 88.
MS m/z(ESI):417.2[M+H] + .
Example 100
3- ((3-exo) -3- ((8-methoxy-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001951
Preparation of 3- ((3-exo) -3- ((8-methoxy-7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):433.2[M+H] + .
Example 101
5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-8-carbonitrile
Figure BDA0002321528230001952
Preparation of 5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-8-carbonitrile refers to example 88.
MS m/z(ESI):428.2[M+H] + .
Example 102
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-pyrano [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001961
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-pyrano [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 4.
MS m/z(ESI):409.2[M+H] + .
Example 103
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-pyrano [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001962
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-pyrano [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):409.2[M+H] + .
Example 104
3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro- [1,4] dioxino [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001963
Preparation of 3- ((3-exo) -3- ((2- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro- [1,4] dioxino [2,3-d ] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 39.
MS m/z(ESI):411.2[M+H] + .
Example 105
3- (5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azatricyclo [3.3.1.13,7] decan-2-yl) propionitrile
Figure BDA0002321528230001971
Preparation of 3- (5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azatricyclo [3.3.1.13,7] decan-2-yl) propionitrile reference example 5.
MS m/z(ESI):429.2[M+H] + .
Example 106
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -6-azabicyclo [3.1.1] heptan-6-yl) propionitrile
Figure BDA0002321528230001972
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -6-azabicyclo [3.1.1] heptan-6-yl) propionitrile reference example 5.
MS m/z(ESI):389.2[M+H] + .
Example 107
3- ((1S, 4S, 5S) -5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azabicyclo [2.2.2] octan-2-yl) propionitrile
Figure BDA0002321528230001981
Preparation of 3- ((1S, 4S, 5S) -5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azabicyclo [2.2.2] octan-2-yl) propionitrile reference is made to example 5.
MS m/z(ESI):403.2[M+H] + .
Example 108
3- ((1S, 4S, 5S) -5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azabicyclo [2.2.1] heptan-2-yl) propionitrile
Figure BDA0002321528230001982
Preparation of 3- ((1S, 4S, 5S) -5- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azabicyclo [2.2.1] heptan-2-yl) propionitrile reference example 5.
MS m/z(ESI):389.2[M+H] + .
Example 109
3- (3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001983
The first step is as follows: preparation of tert-butyl-3- (7-chloro-1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230001991
Tert-butyl-3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (119mg, 0.53mmol), 5, 7-dichloro-1, 6-naphthyridine (100mg, 0.5 mmol), and diisopropylethylamine (95mg, 1.5 mmol) were dissolved in DMSO (4 mL), stirred at room temperature, and then heated to 110 ℃ for a reaction time of 22 hours with stirring. The reaction solution was diluted with ethyl acetate, the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, the collected organic solvent was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography to give the title compound (173mg, 92%).
1 H NMR(400MHz,DMSO-d 6 )δ8.97(dd,J＝4.1,1.1Hz,1H),8.47(d,J＝8.4Hz,1H),7.53(dd,J＝8.5,4.2Hz,1H),7.37(s,1H),4.22(s,2H),3.86(d,J＝12.2Hz,2H),3.34(s,1H),3.31-3.29(m,1H),1.96-1.80(m,4H),1.44(s,9H).
MS m/z(ESI):375.2[M+H] + .
The second step: preparation of 3- (3- (7-chloro-1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230001992
Tert-butyl-3- (7-chloro-1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1699 mg, 0.45mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added with stirring at room temperature, and the resulting reaction mixture was reacted with stirring at room temperature for 30 minutes, and concentrated under reduced pressure to give a brown oil. The obtained brown oily substance was dissolved in anhydrous methanol (2 mL), diisopropylethylamine (0.745mL, 4.5mmol) and acrylonitrile (0.036 mL, 0.54mmol) were added successively with stirring at room temperature, the reaction solution was reacted with stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure to give a crude product, which was isolated and purified by silica gel column chromatography to give the title compound (135mg, 91%).
1 H NMR(400MHz,DMSO-d 6 )δ8.94(dd,J＝4.1,1.1Hz,1H),8.43(d,J＝8.3Hz,1H),7.50(dd,J＝8.5,4.2Hz,1H),7.29(s,1H),3.81(d,J＝10.2Hz,2H),3.36(d,J＝11.6Hz,4H),2.67(t,J＝6.4Hz,2H),2.58(t,J＝6.4Hz,2H),1.85(dd,J＝12.4,6.7Hz,2H),1.80-1.72(m,2H).
MS m/z(ESI):328.2[M+H] + .
The third step: preparation of 3- (3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002001
3- (3- (7-chloro-1, 6-naphthyridin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.153mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylic acid ester (36mg, 0.183mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (7mg, 0.009mmol) and cesium carbonate (650mg, 0.20mmol) were added to an ultra-dry 1, 4-dioxane (5 mL), and the reaction mixture was saturated with dry nitrogen gas, then heated to 110 ℃ with a sealed tube, stirred for reaction for 36 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Redissolved in dichloromethane (2 mL), added trifluoroacetic acid (1 mL), stirred at room temperature for 30 min, concentrated under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (2.7 mg, 5%).
1 H NMR(400MHz,CD 3 OD)δ8.61(d,J＝2.8Hz,1H),8.32(dd,J＝8.3,2.6Hz,1H),7.22-6.99(m,2H),6.07(s,1H),3.73(dd,J＝11.7,1.5Hz,2H),3.51-3.36(m,4H),2.69(qd,J＝8.2,1.7Hz,4H),2.29(s,3H),2.04(s,4H).
MS m/z(ESI):389.3[M+H] + .
Example 110
3- ((3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) -3-azabicyclo [3.2.1] octan-8-yl) amino) propionitrile
Figure BDA0002321528230002002
Preparation of 3- ((3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) -3-azabicyclo [3.2.1] octan-8-yl) amino) propionitrile reference example 109.
MS m/z(ESI):403.2[M+H] + .
Example 111
3- ((3-exo) -3- (methyl (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002011
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002012
The compounds 5, 7-dichloro-1, 6-naphthyridine (200mg, 1.0mmol), tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (264mg, 1.1mmol) and DIPEA (0.5mL, 3.0mmol) were dissolved in dimethyl sulfoxide (3 mL), and the reaction mixture was heated to 120 ℃ and stirred for 30 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was used in the next step without purification.
MS m/z(ESI):403.1[M+H] + .
The second step of reaction: preparation of 3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002013
Tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was dissolved in 4M HCl 1, 4-epoxyhexacyclic compound (10 mL), the resulting reaction mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, the residual oil was dissolved in anhydrous methanol (15 mL), DIPEA (8.24mL, 50mmol) and acrylonitrile (1.32mL, 20mmol) were added in this order, the resulting reaction mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel column to give the title compound (242mg, 68%).
MS m/z(ESI):356.1[M+H] + .
The third step of reaction: preparation of 3- ((3-exo) -3- (methyl (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002021
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.14mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylic acid ester (42mg, 0.21mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (24mg, 0.03mmol) and Cemogen (138mg, 0.42mmol) were added to ultra-dried 1, 4-epoxyhexacyclic compound (5 mL), and the reaction mixture was saturated with dry nitrogen and then heated to 100 ℃ with a sealed tube and stirred for 26 hours. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, and separated by prep-HPLC to give the title compound (23.7 mg, 41%).
1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.82(s,1H),8.65(dd,J＝4.1,1.3Hz,1H),8.13(d,J＝8.1Hz,1H),7.19(s,1H),7.06(dd,J＝8.3,4.2Hz,1H),5.96(s,1H),4.27-4.14(m,1H),3.33-3.31(m,2H),2.93(s,3H),2.61(dd,J＝11.0,5.0Hz,4H),2.20(s,3H),1.94(t,J＝11.1Hz,2H),1.87-1.79(m,2H),1.68-1.60(m,2H),1.52(d,J＝7.7Hz,2H).
MS m/z(ESI):417.3[M+H] + .
Example 112
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002022
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 5.
MS m/z(ESI):404.2[M+H] + .
Example 113
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002031
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):402.2[M+H] + .
Example 114
3- (3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002032
Preparation of 3- (3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):403.2[M+H] + .
Example 115
3- (3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002041
Preparation of 3- (3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):453.2[M+H] + .
Example 116
3- ((3-exo) -3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-5-carbonyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002042
Preparation of 3- ((3-exo) -3- (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridine-5-carbonyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):416.2[M+H] + .
Example 117
3- ((3-exo) -3- ((S) -hydroxy (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002043
Preparation of 3- ((3-exo) -3- ((S) -hydroxy (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) methyl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):418.2[M+H] + .
Example 118
N7- (5-methyl-1H-pyrazol-3-yl) -N5- ((3-exo) -8- (oxetan-3-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridine-5, 7-diamine
Figure BDA0002321528230002051
Preparation of N7- (5-methyl-1H-pyrazol-3-yl) -N5- ((3-exo) -8- (oxetan-3-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridine-5, 7-diamine reference example 111.
MS m/z(ESI):420.2[M+H] + .
Example 119
(cis) -3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) cyclobutane-1-carbonitrile
Figure BDA0002321528230002052
Preparation of (cis) -3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) cyclobutane-1-carbonitrile reference example 111.
MS m/z(ESI):429.2[M+H] + .
Example 120
(trans) -3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) cyclobutane-1-carbonitrile
Figure BDA0002321528230002061
Preparation of (trans) -3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) cyclobutane-1-carbonitrile reference example 111.
MS m/z(ESI):429.2[M+H] + .
Example 121
(cis) -3- (((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclobutane-1-carbonitrile
Figure BDA0002321528230002062
Preparation of (cis) -3- (((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclobutane-1-carbonitrile reference example 111.
MS m/z(ESI):443.3[M+H] + .
Example 122
(trans) -3- (((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclobutane-1-carbonitrile
Figure BDA0002321528230002071
Preparation of (trans) -3- (((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclobutane-1-carbonitrile reference example 111.
MS m/z(ESI):443.3[M+H] + .
Example 123
N5- ((3-exo) -8- (azetidin-3-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -N7- (5-methyl-1H-pyrazol-3-yl) -1, 6-naphthyridine-5, 7-diamine
Figure BDA0002321528230002072
Preparation of N5- ((3-exo) -8- (azetidin-3-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -N7- (5-methyl-1H-pyrazol-3-yl) -1, 6-naphthyridine-5, 7-diamine reference is made to example 111.
MS m/z(ESI):419.3[M+H] + .
Example 124
N7- (5-methyl-1H-pyrazol-3-yl) -N5- ((3-exo) -8- (piperidin-4-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridine-5, 7-diamine
Figure BDA0002321528230002073
Preparation of N7- (5-methyl-1H-pyrazol-3-yl) -N5- ((3-exo) -8- (piperidin-4-ylmethyl) -8-azabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridine-5, 7-diamine reference example 111.
MS m/z(ESI):447.3[M+H] + .
Example 125
3- (3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) azetidin-1-yl) propionitrile
Figure BDA0002321528230002081
Preparation of 3- (3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) azetidin-1-yl) propionitrile reference is made to example 111.
MS m/z(ESI):458.3[M+H] + .
Example 126
1- (((3-exo) -3- (methyl (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002082
Preparation of 1- (((3-exo) -3- (methyl (7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 111.
MS m/z(ESI):522.2[M+H] + .
Example 127
(3-exo) -N- (2-cyanoethyl) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-sulfonamide
Figure BDA0002321528230002091
Preparation of (3-exo) -N- (2-cyanoethyl) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-sulfonamide reference example 111.
MS m/z(ESI):496.2[M+H] + .
Example 128
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002092
ExactMass:537.2
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile is according to example 2.
MS m/z(ESI):538.2[M+H] + .
Example 129
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002101
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile is referred to example 2.
MS m/z(ESI):524.2[M+H] + .
Example 130
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002102
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile is according to example 2.
MS m/z(ESI):541.2[M+H] + .
Example 131
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002103
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 3.
MS m/z(ESI):527.2[M+H] + .
Example 132
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002111
The first step is as follows: preparation of (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0002321528230002112
2, 4-dichlorothieno [2,3-d ] pyrimidine (100mg, 0.49mmol), (3-amino-1H-pyrazol-5-yl) methanol (55mg, 0.49mmol), DIPEA (190mg, 1.47mmol) were added to N' N-dimethylformamide (2 mL), and the reaction mixture was stirred at 70 ℃ overnight. Concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (100mg, 73%).
MS m/z(ESI):282.0[M+H] + .
The second step: preparation of tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002113
Adding (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg, 0.36mmol), tert-butyl (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (135mg, 0.53mmol) and DIPEA (140mg, 1.08mmol) into n-butanol (2.5 mL), mixing uniformly, reacting at the temperature of 150 ℃ for 10 hours under microwave, cooling to room temperature, concentrating the reaction liquid under reduced pressure, and separating and purifying the obtained crude product by using a flash silica gel column chromatography to obtain a white solid (70mg, 39%).
MS m/z(ESI):500.1[M+H] + .
The third step: 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidine-2-
Preparation of the radical) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002121
Dioxane hydrochloride (4N, 2.5 mL) was slowly added dropwise to a solution of tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylic acid ester (70mg, 0.14mmol) in methanol (10 mL), reacted at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, the crude product was dissolved in DMF (5 mL), and DIPEA (0.3 mL) and 3-cyanoazetidine-1-sulfonyl chloride (22mg, 0.12mmol) were added in an ice-water bath at 0 ℃ and reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and separated and purified by prep-HPLC to give the objective compound as a white solid (9.7mg, 13%)
1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),7.68(d,J＝4.4Hz,1H),7.04(d,J＝6.0Hz,1H),6.52-6.54(m,1H),5.53-5.55(m,1H),5.33-5.35(m,1H),4.44(d,J＝5.2Hz,2H),4.05-4.01(m,4H),3.94-3.90(m,2H),382-3.79(m,1H),2.89(d,J＝8.4Hz,3H),2.08-1.68(m,11H).
MS m/z(ESI):544.1[M+H] + .
Example 133
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002131
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 2.
MS m/z(ESI):545.2[M+H] + .
Example 134
1- (((3-exo) -3- ((5- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-7-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002132
Preparation of 1- (((3-exo) -3- ((5- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-7-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 132.
MS m/z(ESI):538.2[M+H] + .
Example 135
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) pyrido [3,4-b ] pyrazin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002133
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) pyrido [3,4-b ] pyrazin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 2.
MS m/z(ESI):539.2[M+H] + .
Example 136
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002141
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 3.
MS m/z(ESI):544.2[M+H] + .
Example 137
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002142
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 132.
MS m/z(ESI):561.1[M+H] + .
Example 138
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1,3, 4-thiadiazol-2-yl) amino) quinazolin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002151
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1,3, 4-thiadiazol-2-yl) amino) quinazolin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 132.
MS m/z(ESI):556.2[M+H] + .
Example 139
1- (((3-exo) -3- ((6- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002152
Preparation of 1- (((3-exo) -3- ((6- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile is according to example 2.
MS m/z(ESI):529.2[M+H] + .
Example 140
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002161
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 2.
MS m/z(ESI):530.2[M+H] + .
Example 141
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002162
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 132.
MS m/z(ESI):425.2[M+H] + .
Example 142
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002163
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 132.
MS m/z(ESI):442.1[M+H] + .
Example 143
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002171
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) thiazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 132.
MS m/z(ESI):436.2[M+H] + .
Example 144
3- ((3-exo) -3- ((6- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002172
Preparation of 3- ((3-exo) -3- ((6- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 2.
MS m/z(ESI):424.2[M+H] + .
Example 145
3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002181
Preparation of 3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) imidazo [1,2-c ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 2.
MS m/z(ESI):425.2[M+H] + .
Example 146
N- (5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) -5-methyl-1H-pyrazole-3-carboxamide
Figure BDA0002321528230002182
Preparation of N- (5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) -5-methyl-1H-pyrazole-3-carboxamide reference example 1.
MS m/z(ESI):431.2[M+H] + .
Example 147
3- ((3-exo) -3- ((2- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002183
Preparation of 3- ((3-exo) -3- ((2- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 3.
MS m/z(ESI):376.2[M+H] + .
Example 148
3- ((3-exo) -3- (3- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002191
Preparation of 3- ((3-exo) -3- (3- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):377.2[M+H] + .
Example 149
3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002192
Preparation of 3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):378.2[M+H] + .
Example 150
3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002201
Preparation of 3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):394.2[M+H] + .
Example 151
3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002202
Preparation of 3- ((3-exo) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):378.2[M+H] + .
Example 152
3- ((3-exo) -3- (2-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002203
Preparation of 3- ((3-exo) -3- (2-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-imidazo [4,5-b ] pyrazin-1-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):392.2[M+H] + .
Example 153
3- ((3-exo) -3- (7-methoxy-5- ((5-methyl-1H-pyrazol-3-yl) amino) -3H-imidazo [4,5-b ] pyridin-3-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002211
Preparation of 3- ((3-exo) -3- (7-methoxy-5- ((5-methyl-1H-pyrazol-3-yl) amino) -3H-imidazo [4,5-b ] pyridin-3-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):407.2[M+H] + .
Example 154
3- ((3-exo) -3- (6-methoxy-8-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-9-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002212
Preparation of 3- ((3-exo) -3- (6-methoxy-8-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) -9H-purin-9-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):422.2[M+H] + .
Example 155
3- ((3-exo) -3- (4-methoxy-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002221
Preparation of 3- ((3-exo) -3- (4-methoxy-2- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):407.2[M+H] + .
Example 156
3- ((3-exo) -3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -6-morpholino-9H-purin-9-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002222
Preparation of 3- ((3-exo) -3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -6-morpholino-9H-purin-9-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 111.
MS m/z(ESI):463.3[M+H] + .
Example 157
3- ((1R, 5S) -3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-b ] [1,2,4] triazin-7-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002223
Preparation of 3- ((1R, 5S) -3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) imidazo [1,2-b ] [1,2,4] triazin-7-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile reference example 109.
MS m/z(ESI):379.2[M+H] + .
Example 158
3- ((1R, 5S) -3- (5- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002231
Preparation of 3- ((1R, 5S) -3- (5- ((5-methyl-1H-pyrazol-3-yl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile reference example 109.
MS m/z(ESI):378.2[M+H] + .
Example 159
3- ((1R, 5S) -3- (3- ((5-methyl-1H-pyrazol-3-yl) amino) quinoxalin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002232
Preparation of 3- ((1R, 5S) -3- (3- ((5-methyl-1H-pyrazol-3-yl) amino) quinoxalin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 109.
MS m/z(ESI):389.2[M+H] + .
Example 160
2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-carbonitrile
Figure BDA0002321528230002233
The first step of reaction: preparation of tert-butyl (3-exo) -3- ((7- ((5-cyanothiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002241
Tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (194mg, 0.5mmol), 2-aminothiazole-5-carbonitrile (125mg, 1.0mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (196mg, 0.25mmol) and carbonic acid (489mg, 1.5mmol) were added to 10mL of an ultradry 1, 4-epoxyhexacyclic ring, and the reaction mixture was saturated with dry nitrogen gas and heated to 150 ℃ by microwave stirring for 9 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to isolate the title compound (151.6 mg, 63%).
MS m/z(ESI):478.1[M+H] + .
The second step of reaction: preparation of 2- ((5- (((3-exo) -8- (2-cyanoethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazole-5-carbonitrile
Figure BDA0002321528230002242
Tert-butyl (3-exo) -3- ((7- ((5-cyanothiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (180mg, 0.377mmol) was dissolved in 4M HCl in 1.4-dioxane (20 mL) and the reaction was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was redissolved in anhydrous methanol (10 mL), DIPEA (1.86mL, 11.3 mmol) and acrylonitrile (0.25mL, 3.77mmol) were added in this order, and the resulting reaction mixture was stirred at room temperature for 105 minutes. The solvent was removed by concentration under reduced pressure, and the residue was successively subjected to silica gel column chromatography and prep-HPLC to give the title compound (8.6 mg, 2.0%).
1 H NMR(400MHz，DMSO-d 6 )δ11.91(s，1H)，8.76(d，J＝3.2Hz，1H)，8.65(d，J＝8.4Hz，1H)，8.23(s，1H)，7.68(d，J＝8.5Hz，1H)，7.23(dd，J＝8.3，4.3Hz，1H)，6.59(s，1H)，4.76(td，J＝17.4，8.7Hz，1H)，3.38(s，2H)，2.65(s，4H)，2.07-1.72(m，8H).
MS m/z(ESI):431.1[M+H] + .
Example 161
3- ((3-exo) -3- ((7- ((5- (2-hydroxyethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002251
Preparation of 3- ((3-exo) -3- ((7- ((5- (2-hydroxyethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 2.
1 H NMR(400MHz，DMSO-d 6 )δ10.78(s，1H)，8.67(d，J＝4.8Hz，1H)，8.55(d，J＝7.1Hz，1H)，7.45(d，J＝7.8Hz，1H)，7.12-7.04(m，2H)，6.47(s，1H)，4.87-4.77(m，2H)，3.61(dd，J＝12.7，7.0Hz，2H)，3.34(s，2H)，2.85-2.79(m，2H)，2.65(s，4H)，1.88(ddd，J＝29.8，26.6，7.6Hz，8H).
MS m/z(ESI):450.2[M+H] + .
Example 162
3- ((3-exo) -3- ((7- ((5- (1-hydroxyethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002252
The first step of reaction: preparation of 1- (2-aminothiazol-5-yl) ethan-1-ol
Figure BDA0002321528230002253
Dissolving 2-aminothiazole-5-formaldehyde (256mg, 2.0mmol) in dry tetrahydrofuran (10 mL), cooling to 0 ℃, dropwise adding magnesium methylbromide (3M diethyl ether solution, 3.5mL, 10mmol) into the reaction liquid under the protection of nitrogen, and continuously stirring the reaction liquid at 0 ℃ for reacting for 70 minutes. The reaction mixture was quenched with water, extracted with ethyl acetate, and the ethyl acetate layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (150mg, 52%).
MS m/z(ESI):145.2[M+H] + .
The second step of reaction: preparation of 3- ((3-exo) -3- ((7- ((5- (1-hydroxyethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002261
3- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile (50mg, 0.146mmol), 1- (2-aminothiazol-5-yl) ethan-1-ol (42mg, 0.292mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (57mg, 0.3mmol) and Cbz 07 (143mg, 0.438mmol) are added to an ultradry 1, 4-epoxyhexacyclic compound (5 mL), and the reaction mixture is saturated with dry nitrogen and heated to 140 ℃ with microwaves and the reaction is stirred for 4 hours. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, and isolated by prep-HPLC to give the title compound (1.9 mg, 3%).
1 H NMR(400MHz，DMSO-d 6 )δ10.79(s，1H)，8.67(d，J＝3.0Hz，1H)，8.56(d，J＝8.0Hz，1H)，7.44(d，J＝8.4Hz，1H)，7.16-7.07(m，2H)，6.49(s，1H)，5.29(d，J＝4.2Hz，1H)，4.92-4.81(m，2H)，3.34(s，2H)，2.65(s，4H)，1.93(s，4H)，1.81(d，J＝9.9Hz，4H)，1.44(d，J＝6.4Hz，3H).
MS m/z(ESI):450.2，452.0[M+H] + .
Example 163
3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002271
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002272
5, 7-dichloro-1, 6-naphthyridine (300mg, 1.51mmol), (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester oxalate (750mg, 2.26mmol), DIPEA (580mg, 4.53mmol) were added to DMSO (5 mL), and after uniform mixing, the reaction mixture was reacted at 110 ℃ overnight, cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (500mg, 82%).
MS m/z(ESI):403.1[M+H] + .
The second step: preparation of tert-butyl (3-exo) -3- ((7- ((5-formylthiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002273
Tert-butyl (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (200mg, 0.5 mmol), 2-aminothiazole-5-carbaldehyde (96mg, 0.75mmol), tris (dibenzylideneacetone) dipalladium (46mg, 0.05mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (60mg, 0.1mmol), cesium carbonate (490mg, 1.5 mmol) were added to a solution of 1, 4-dioxane (5 mL), and reacted for 3 hours under microwave heating at 160 ℃ with N2 protection. After cooling to room temperature, the reaction mixture was concentrated under pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (150mg, 61%).
MS m/z(ESI):495.1[M+H] + .
The third step: preparation of tert-butyl (3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002281
To tert-butyl (3-exo) -3- ((7- ((5-formylthiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (150mg, 0.3mmol) was added methanol (10 mL), sodium borohydride (45mg, 1.2mmol) was slowly added to the reaction solution at 0 ℃ and after 0.5 hour, water (0.2 mL) was added to quench, the reaction solution was concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (100mg, 67%).
MS m/z(ESI):497.2[M+H] + .
The fourth step: preparation of 3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002282
(3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester (100mg, 0.2 mmol) was added to methanol (10 mL), dioxane hydrochloride solution (4N, 2 mL) was slowly added to the reaction solution, the reaction was reacted at room temperature for 1 hour, and concentrated under reduced pressure, a mixed solution of acrylonitrile (0.2 mL), DIPEA (0.2 mL), methanol (10 mL) was added to the resulting crude product (100 mg), the reaction was reacted at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting crude product was isolated and purified by prep-HPLC to give the title compound as a white solid (19.2 mg, 15%).
1 H NMR(400MHz，DMSO-d 6 )δ10.88(s，1H)，8.69(t，J＝2.8Hz，1H)，8.58(d，J＝8.0Hz，1H)，7.32(d，J＝8.0Hz，1H)，7.18-7.12(m，2H)，6.50(s，1H)，5.18-5.09(m，2H)，4.50(d，J＝5.2Hz，2H)，3.03-2.92(m，4H)，2.63(t，J＝6.4Hz，2H)，2.24-2.16(m，1H)，1.98-1.87(m，6H)，1.73-1.67(m，3H).
MS m/z(ESI):450.1[M+H] + .
Example 164
1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (pyrrolidin-1-yl) ethan-1-one
Figure BDA0002321528230002291
Preparation of 1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (pyrrolidin-1-yl) ethan-1-one refers to example 163.
MS m/z(ESI):508.2[M+H] + .
Example 165
1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2- (piperidin-1-yl) ethan-1-one
Figure BDA0002321528230002292
Preparation of 1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2- (piperidin-1-yl) ethan-1-one refers to example 163.
1 H NMR(400MHz，DMSO-d 6 )δ10.89(s，1H)，8.68(dd，J＝4.0，1.2Hz，1H)，8.52(d，J＝8.4Hz，1H)，7.46(d，J＝8.4Hz，1H)，7.19-7.11(m，2H)，6.52(s，1H)，5.18-5.09(m，2H)，4.56-4.54(m，4H)，3.16-3.13(m，1H)，3.03-3.00(m，1H)，2.51-2.39(m，4H)，2.09-1.76(m，8H)，1.52-1.50(m，4H)，1.38-1.35(m，2H).
MS m/z(ESI):508.1[M+H] + .
Example 166
2, 2-difluoro-1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002301
The first step is as follows: preparation of 1- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2, 2-difluoroethan-1-one
Figure BDA0002321528230002302
Compound (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg, 0.771mmol) was added to methanol (2 mL), HCl in methanol (2mL, 4M) was added at room temperature, and then stirred at room temperature for 1 hour. The reaction solution was concentrated to give an orange solid.
The above solid (100mg, 0.251mmol), 2-difluoroacetic acid (29mg, 0.301mmol) and DIPEA (143mg, 0.377 mmol) were each added to DCM (2 mL), and HATU (143mg, 113mmol) was added portionwise at room temperature, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was slurried with a mixed solution of methanol and water (2 mL each) to give the title compound as a white solid (33mg, 36%).
MS m/z(ESI):367.1[M+H] + .
The second step is that: preparation of 2, 2-difluoro-1- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002311
1- ((3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2, 2-difluoroethan-1-one (72mg, 0.197mmol), (2-aminothiazol-5-yl) methanol (38mg, 0.295mmol), cesium carbonate (128mg, 0.394mmol), chlorine (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (X-Phos Pd G2) (31mg, 0.0394mmol), XPhos (19mg, 0.0394mmol) were added to dioxane (3.5 mL), respectively. After nitrogen substitution was carried out three times, the temperature was raised to 90 ℃ and the reaction was stirred for 16 hours. The reaction was concentrated under reduced pressure, and the residue was subjected to preliminary purification by silica gel column chromatography and then purified by prep-HPLC to give the title compound as a yellow solid (7.4mg, 8%).
1 H NMR(400MHz，DMSO-d 6 )δ10.91(s，1H)，8.69(dd，J＝4.3，1.6Hz，1H)，8.50(d，J＝8.4Hz，1H)，7.52(d，J＝8.6Hz，1H)，7.19(s，1H)，7.13(dd，J＝8.4，4.3Hz，1H)，6.69(t，J＝53.0Hz，1H)，6.54(s，1H)，5.31-5.04(m，2H)，4.63-4.49(m，4H)，2.20-1.72(m，8H).
MS m/z(ESI):461.1[M+H] + .
Example 167
(2- ((5- (((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazol-5-yl) methanol
Figure BDA0002321528230002312
The first step is as follows: preparation of 7-chloro-N- ((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] oct-3-yl) -1, 6-naphthyridin-5-amine
Figure BDA0002321528230002321
Compound (3-exo) -3- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (200mg, 0.514mmol) was dissolved in methanol (1.6 mL), HCl in dioxane (1.2mL, 4M) was added at room temperature, and then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with N, N-dimethylformamide (2 mL), and cesium carbonate (670mg, 2.06mmol) and 1-bromo-2-fluoroethane (131mg, 1.03mmol) were added to stir at 100 ℃ for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the organic solvent was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography to give the title compound as a brown solid (108mg, 63%).
MS m/z(ESI):335.1[M+H] + .
The second step is that: preparation of (2- ((5- (((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] oct-3-yl) amino) -1, 6-naphthyridin-7-yl) amino) thiazol-5-yl) methanol
Figure BDA0002321528230002322
7-chloro-N- ((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridin-5-amine (60mg, 0.179mmol), (2-aminothiazol-5-yl) methanol (47mg, 0.358mmol), cesium carbonate (117mg, 0.358mmol), chloro (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (X-Phos Pd G2) (28mg, 0.0358mmol), XPhos (17mg, 0.0358mmol) were added to dioxane (2 mL), respectively. After nitrogen substitution was carried out three times, the temperature was raised to 85 ℃ and the reaction was stirred for 16 hours. The reaction solution was cooled, diluted with methanol, then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow solid (6.0 mg, 8%).
1 H NMR(400MHz，DMSO-d 6 )δ10.86(s，1H)，8.68(dd，J＝4.3，1.6Hz，1H)，8.54(d，J＝8.4Hz，1H)，7.45(d，J＝8.6Hz，1H)，7.18(s，1H)，7.11(dd，J＝8.4，4.3Hz，1H)，6.49(s，1H)，5.17(t，J＝5.3Hz，1H)，4.95-4.79(m，1H)，4.64-4.53(m，3H)，4.46(t，J＝5.2Hz，1H)，2.77(t，J＝5.2Hz，1H)，2.71(t，J＝5.3Hz，1H)，2.00-1.74(m，8H).
MS m/z(ESI):429.1[M+H] + .
Example 168
3- ((3-exo) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002331
Preparation of 3- ((3-ex) -3- ((7- ((5- (hydroxymethyl) thiazol-2-yl) amino) -1, 6-naphthyridin-5-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 2.
MS m/z(ESI):437.2[M+H] + .
Example 169
3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002332
The first step is as follows: preparation of 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0002321528230002333
2, 4-dichloro-7-methoxyquinazoline (500mg, 2.18mmol), 5-methyl-1H-pyrazol-3-amine (223mg, 2.29mmol) and DIPEA (592mg, 4.58mmol) were each added to absolute ethanol (10 mL), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, and the filter cake was washed with acetonitrile (5 mL) and dried in vacuo to give the title compound as a white solid (355mg, 56%).
MS m/z(ESI):290.1[M+H] + .
The second step is that: preparation of tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002341
The compound 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (355mg, 1.23mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (421mg, 1.47mmol) and DIPEA (475mg, 3.68mmol) were mixed in N-butanol (7 mL), and the mixture was heated to 150 ℃ with a microwave and stirred for reaction for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a white solid (259mg, 44%).
MS m/z(ESI):480.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002342
Tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (259mg, 0.540mmol) was dissolved in methanol (3 mL), 4M HCl in 1, 4-dioxane (4 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (3 mL), DIPEA (349mg, 2.70mmol) and acrylonitrile (43mg, 0.810mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 0.5 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a white solid (76.8mg, 33%).
1 H NMR(400MHz，Methanol-d 4 )δ8.12(s，1H)，7.14-6.75(m，2H)，6.50(s，1H)，4.50-4.21(m，1H)，3.92(s，3H)，3.41(s，2H)，2.91-2.55(m，4H)，2.34(s，3H)，2.14-1.50(m，7H)，1.40-1.23(m，1H).
MS m/z(ESI):433.2[M+H] + .
Example 170
3- ((3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002351
The first step is as follows: preparation of 7-bromo-2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0002321528230002352
7-bromo-2, 4-dichloroquinazoline (3.36g, 12.1mmol), 5-methyl-1H-pyrazol-3-amine (1.29g, 13.3mmol) and TEA (2.57g, 25.4 mmol) were added to absolute ethanol (67 mL), respectively, and stirred at room temperature for 16 hours. The reaction was filtered, and the filter cake was washed with absolute ethanol (20 mL) and dried in vacuo to give the title compound as a white solid (4.17g, 100%).
The second step: preparation of tert-butyl (3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002361
The compounds 7-bromo-2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (500mg, 1.48mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (465mg, 1.62mmol) and DIPEA (591mg, 4.58mmol) were mixed in NMP (5 mL), and the mixture was heated to 130 ℃ with a microwave and stirred for reaction for 4 hours. The reaction mixture was cooled to room temperature, and then poured into 25mL of ice water and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with acetonitrile (2 mL) and dried under reduced pressure to give the title compound as a gray solid (877mg, 100%).
The third step: preparation of 3- ((3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002362
Tert-butyl (3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (220mg, 0.416 mmol) was dissolved in methanol (2 mL), 4M HCl 1, 4-dioxane (2 mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2 mL), DIPEA (269mg, 2.08mmol) and acrylonitrile (66mg, 1.25mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a white solid (17.4 mg, 9%).
1 H NMR(400MHz，CD 3 OD)δ7.94(d，J＝8.8Hz，1H)，7.74-7.37(m，1H)，7.24(dd，J＝8.9，2.0Hz，1H)，6.59(s，0.8H)，5.92(s，0.2H)，4.51-4.12(m，1H)，3.42-3.35(m，2H)，2.75(t，J＝6.9Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.31(s，3H)，2.09-1.61(m，8H).
MS m/z(ESI):481.1[M+H] + .
Example 171
3- ((3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002371
The first step is as follows: preparation of 2, 7-dichloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0002321528230002372
2,4, 7-trichloroquinazoline (2.0g, 8.58mmol), 5-methyl-1H-pyrazol-3-amine (915mg, 9.42mmol) and TEA (1.82g, 18.0 mmol) were added to anhydrous ethanol (40 mL) and stirred at room temperature for 16 hours, respectively. The reaction was filtered, and the filter cake was washed with anhydrous ethanol (5 mL) and dried under vacuum to give the title compound as a white solid (2.5g, 99%).
MS m/z(ESI):294.0[M+H] + .
The second step is that: preparation of tert-butyl (3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002373
The compounds 2, 7-dichloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (500mg, 1.70mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (535mg, 1.87mmol) and DIPEA (681mg, 5.27mmol) were mixed in NMP (7 mL), and the mixture was heated by microwave to 180 ℃ and stirred for reaction for 2 hours. After the reaction solution was cooled to room temperature, it was added to ice water and stirred, and the precipitated solid was filtered. The filter cake was washed with water, dried in vacuo, and then purified by silica gel column chromatography to give the title compound as a white solid (405mg, 49%).
MS m/z(ESI):484.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002381
Tert-butyl (3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (405mg, 0.837mmol) was dissolved in methanol (4 mL), 4M HCl 1, 4-dioxane (2.5 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (4 mL), DIPEA (486 mg, 3.77mmol) and acrylonitrile (53mg, 1.00mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was preliminarily separated and purified by silica gel column chromatography and then by prep-HPLC to give the title compound as a white solid (40mg, 11%).
1 H NMR(400MHz，Methanol-d 4 )δ8.02(d，J＝8.8Hz，1H)，7.54-7.22(m，1H)，7.14-7.07(m，1H)，6.71-6.49(m，0.6H)，6.05-5.76(m，0.4H)，4.44-4.17(m，1H)，3.40-3.35(m，2H)，2.75(t，J＝7.0Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.46-2.12(m，3H)，2.07-2.00(m，2H)，1.96-1.75(m，4H)，1.71-1.61(m，2H).
MS m/z(ESI):437.2[M+H] + .
Example 172
3- ((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Exact Mass:4202
Figure BDA0002321528230002382
Preparation of 3- ((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 171.
MS m/z(ESI):421.2[M+H] + .
Example 173
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002391
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) pyrido [3,4-d ] pyrimidin-4-amine
Figure BDA0002321528230002392
2, 4-dichloropyrido [3,4-d ] pyrimidine (120mg, 0.6 mmol), 5-methyl-1H-pyrazol-3-amine (64mg, 0.66mmol) and DIPEA (150mg, 1.2mmol) were added to N, N-dimethylformamide (4 mL), and after the reaction mixture was mixed uniformly, the mixture was stirred overnight under oil bath heating at 70 ℃. Concentrated under reduced pressure, and the resulting crude product was added methanol (5 mL) and a solid precipitated, filtered, and dried to give the title compound as a yellow solid (140mg, 89%).
MS m/z(ESI):261.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002393
2, 4-dichloropyrido [3,4-d ] pyrimidine (100mg, 0.22mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (95mg, 0.33mmol), DIPEA (85mg, 0.66mmol) were added to n-butanol (2 mL), the reaction was mixed well, reacted for 16 hours under microwave heating at 150 ℃ and cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a pale yellow solid (40mg, 40%).
MS m/z(ESI):451.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002401
Methanol (10 mL) was added to tert-butyl- (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (40mg, 0.09mmol), the reaction mixture was uniformly mixed, and after that, dioxane hydrochloride solution (4 n, 2ml) was slowly dropped into the reaction mixture, reacted at room temperature for 2 hours, and concentrated under reduced pressure. The resulting crude product was added to a mixed solution of methanol (5 mL), DIPEA (0.5 mL), and acrylonitrile (1 mL) and reacted at room temperature for 2 hours. Concentration under reduced pressure and isolation and purification by prep-HPLC afforded the title compound as a yellow solid (5 mg, 14%).
1 H NMR(400MHz，CD 3 OD)δ9.50-9.38(m，1H)，8.96-8.91(m，2H),7.47-7.45(m，1H)，5.05-5.02(m，2H)，4.10(s，2H)，3.94(s，1H)，3.53-3.48(s，2H)，3.14-3.08(m，3H)，2.84-2.40(m，8H).
MS m/z(ESI):404.2[M+H] + .
Example 174
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002402
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 169.
1 H NMR(400MHz，CD 3 OD)δ8.46-8.36(m，1H)，7.86-7.60(m，1H)，7.55(dd，J＝8.5，4.2Hz，1H)，6.81(s，0.8H)，5.99(s，0.2H)，4.54-4.17(m，1H)，3.47-3.35(m，2H)，2.76(t，J＝7.0Hz，2H)，2.62(t，J＝7.0Hz，2H)，2.41-2.21(m，3H)，2.13-2.01(m，2H)，1.97-1.81(m，4H)，1.75-1.64(m，2H).
MS m/z(ESI):404.2[M+H] + .
Example 175
3- ((3-exo) -3- ((5-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002411
Preparation of 3- ((3-exo) -3- ((5-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
1 H NMR(400MHz，DMSO-d 6 )δ12.24(s，1H)，9.62(s，1H)，7.45(t，J＝8.0Hz，1H)，7.33-6.92(m，3H)，6.92-6.55(m，1H)，4.32-4.15(m，1H)，3.33-3.25(m，2H)，2.68-2.56(m，4H)，2.26(s，3H)，2.00-1.85(m，2H)，1.83-1.54(m，6H).
MS m/z(ESI):437.2[M+H] + .
Example 176
3- ((3-exo) -3- ((8-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002412
Preparation of 3- ((3-exo) -3- ((8-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
1 H NMR(400MHz，Methanol-d 4 )δ7.86(d，1H)，7.44(d，J＝7.1Hz，1H)，7.03(t，J＝7.7Hz，1H)，6.70-6.54(m，0.6H)，5.96-5.84(m，0.4H)，4.49-4.32(m，1H)，3.46-3.36(m，2H)，2.75(t，J＝6.9Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.48(s，3H)，2.38-2.17(m，3H)，2.10-1.89(m，4H)，1.88-1.77(m，2H)，1.64(t，J＝12.0Hz，2H).
MS m/z(ESI):417.2[M+H] + .
Example 177
3- ((3-exo) -3- ((8-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002421
Preparation of 3- ((3-exo) -3- ((8-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
1 H NMR(400MHz，Methanol-d 4 )δ8.01(s，1H)，7.69(d，J＝7.6Hz，1H)，7.09(s，1H)，6.83-5.77(m，1H)，4.52-4.26(m，1H)，3.57-3.36(m，2H)，2.94-2.71(m，2H)，2.71-2.53(m，2H)，2.32(s，3H)，2.19-1.49(m，8H).
MS m/z(ESI):437.2[M+H] + .
Example 178
3- ((3-exo) -3- ((6-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002422
Preparation of 3- ((3-exo) -3- ((6-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
1 H NMR(400MHz，Methanol-d 4 )δ8.15(d，J＝2.3Hz，1H)，7.54(d，J＝8.8Hz，1H)，7.49-7.21(m，1H)，6.72-6.46(m，0.6H)，6.08-5.75(m，0.4H)，4.46-4.20(m，1H)，3.41-3.36(m，2H)，2.76(t，J＝7.0Hz，2H)，2.62(t，J＝7.0Hz，2H)，2.42-2.22(m，3H)，2.08-2.01(m，2H)，1.97-1.77(m，4H)，1.72-1.61(m，2H).
MS m/z(ESI):437.2[M+H] + .
Example 179
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002431
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002432
Reacting tert-butyl (3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1]Octane-8-carboxylate (400mg, 0.758mmol), 3-pyridineboronic acid (187mg, 1.52mmol), pd (dppf) Cl 2 (110mg, 0.152mmol) and cesium carbonate (740 g, 2.27mmol) were added to a mixed solvent of dioxane (8 mL) and water (0.8 mL), and the mixture was heated to 100 ℃ under nitrogen protection and stirred for 1 hour. After the reaction solution was concentrated, the residue was separated and purified by silica gel column chromatography to give the title compound as a pale yellow colloid (160mg, 40%).
The second step is that: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002441
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (160mg, 0.302mmol) was dissolved in methanol (4 mL), 4M HCl 1, 4-dioxane (4 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2 mL), DIPEA (195mg, 1.51mmol) and acrylonitrile (48mg, 0.906mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction, concentration under reduced pressure, preliminary separation and purification of the residue by silica gel column chromatography to give a gray solid, slurried with N, N-dimethylformamide/acetonitrile (2 mL/4 mL), filtered off solid, slurried with N, N-dimethylformamide/acetonitrile (1.1 mL/2.2 mL), filtered off solid, and dried under vacuum to give the title compound as a white solid (49mg, 34%).
1 H NMR(400MHz，CD 3 OD)δ8.90(d，J＝2.3Hz，1H)，8.59(dd，J＝4.9，1.6Hz，1H)，8.31-8.08(m，2H)，7.84-7.40(m，3H)，6.63(s，0.8H)，5.94(s，0.2H)，4.49-4.26(m，1H)，3.45-3.37(m，2H)，2.77(t，J＝6.9Hz，2H)，2.63(t，J＝6.9Hz，2H)，2.34(s，3H)，2.13-1.63(m，8H).
MS m/z(ESI):480.2[M+H] + .
Example 180
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002442
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 179.
1 H NMR(400MHz，CD 3 OD)δ8.73-8.58(m，2H)，8.21(d，J＝8.5Hz，1H)，7.95-7.64(m，3H)，7.59-7.49(m，1H)，6.64(s，1H)，4.49-4.22(m，1H)，3.45-3.35(m，2H)，2.77(t，J＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.33(s，3H)，2.16-1.58(m，8H).
MS m/z(ESI):480.2[M+H] + .
Example 181
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-2-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002451
Preparation of 3- ((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 179.
MS m/z(ESI):480.3[M+H] + .
Example 182
3- ((3-exo) -3- ((7- (5-methoxypyridin-3-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002452
Preparation of 3- ((3-exo) -3- ((7- (5-methoxypyridin-3-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 179.
1 H NMR(400MHz，CD 3 OD)δ8.54-8.41(m，1H)，8.27(d，J＝2.7Hz，1H)，8.17(d，J＝8.5Hz，1H)，7.88-7.56(m，2H)，7.47(dd，J＝8.5，1.8Hz，1H)，6.62(s，1H)，4.49-4.25(m，1H)，3.97(s，3H)，3.44-3.37(m，2H)，2.76(t，J＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.32(s，3H)，2.10-1.64(m，8H).
MS m/z(ESI):510.2[M+H] + .
Example 183
3- ((3-exo) -3- ((7- (6-methoxypyridin-3-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002461
Preparation of 3- ((3-exo) -3- ((7- (6-methoxypyridin-3-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 179.
MS m/z(ESI):510.3[M+H] + .
Example 184
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-phenylquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002462
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-phenylquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 179.
1 H NMR(400MHz，DMSO-d 6 Small amount of CD 3 OD)δ8.47-8.23(m，1H)，7.88-7.69(m，2H)，7.67-7.25(m，5H)，6.92-6.62(m，0.8H)，5.88(s，0.2H)，4.41-4.20(m，1H)，3.58(s，2H)，2.76-2.57(m，4H)，2.38-2.11(m，3H)，2.06-1.47(m，8H).
MS m/z(ESI):479.3[M+H] + .
Example 185
3- ((3-exo) -3- ((7- (1-cyclopropyl-1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002471
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((7- (1-cyclopropyl-1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002472
Tert-butyl (3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.189mmol), (1-cyclopropyl-1H-pyrazol-4-yl) boronic acid (35mg, 0.227mmol), cesium carbonate (185mg, 0.567mmol), chloro (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (X-Phos Pd G2) (15mg, 0.0189mmol) were added to a mixed solvent of dioxane (2 mL) and water (0.4 mL), respectively, replaced with nitrogen three times, and then heated to 100 ℃ for 2 hours with stirring. The reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown oil (60mg, 57%).
The second step is that: preparation of 3- ((3-exo) -3- ((7- (1-cyclopropyl-1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002481
Tert-butyl (3-exo) -3- ((7- (1-cyclopropyl-1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (60mg, 0.108mmol) was dissolved in methanol (2 mL), 4M HCl 1, 4-dioxane (2 mL) was added thereto with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1 mL), DIPEA (70mg, 0.542mmol) and acrylonitrile (17mg, 0.324mmol) were sequentially added thereto, and the resulting reaction mixture was further stirred at room temperature for 16 hours. The reaction was diluted with DCM (30 mL), washed with water (10 mL), concentrated under reduced pressure, and the residue was initially isolated and purified by silica gel chromatography to give the title compound as a gray solid (20mg, 36%).
1 H NMR(400MHz，CD 3 OD)δ8.20(s，1H)，8.06(d，J＝8.3Hz，1H)，7.93(s，1H)，7.72-7.34(m，2H)，6.60(s，1H)，4.45-4.23(m，1H)，3.78-3.67(m，1H)，3.43-3.36(m，2H)，2.76(t，J＝6.8Hz，2H)，2.63(t，J＝6.8Hz，2H)，2.32(s，3H)，2.09-1.64(m，8H)，1.24-1.00(m，4H).
MS m/z(ESI):509.2[M+H] + .
Example 186
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methyl-1H-pyrazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002491
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methyl-1H-pyrazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 185.
1 H NMR(400MHz，CD 3 OD)δ8.09(s，1H)，8.03(d，J＝8.5Hz，1H)，7.93(s，1H)，7.64-7.43(m，1H)，7.38(dd，J＝8.6，1.7Hz，1H)，6.62(s，0.8H)，5.92(s，0.2H)，4.42-4.28(m，1H)，3.95(s，3H)，3.42-3.36(m，2H)，2.76(t，J＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.32(s，3H)，2.08-2.01(m，2H)，2.00-1.80(m，4H)，1.77-1.62(m，2H).
MS m/z(ESI):483.2[M+H] + .
Example 187
3- ((3-exo) -3- ((7- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002492
Preparation of 3- ((3-exo) -3- ((7- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 185.
MS m/z(ESI):515.3[M+H] + .
Example 188
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (thiazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002501
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (thiazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 185.
MS m/z(ESI):486.2[M+H] + .
Example 189
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002502
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 179.
MS m/z(ESI):494.3[M+H] + .
Example 190
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methyl-1H-pyrazol-4-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002511
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methyl-1H-pyrazol-4-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 179.
MS m/z(ESI):497.3[M+H] + .
Example 191
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002512
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002513
Reacting tert-butyl (3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1]Octane-8-carboxylate (300mg, 0.568mmol), morpholine (494mg, 5.68mmol), pd 2 (dba) 3 (104mg, 0.114mmol), davePhos (90mg, 0.227 mmol) and t-BuONa (109mg, 1.14mmol) were added to dioxane (6 mL) respectively, and the mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (20 mL), washed with water (20 mL) and saturated aqueous sodium chloride (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil (66mg, 22%).
The second step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002521
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (66mg, 0.123mmol) was dissolved in methanol (2 mL), 4M HCl 1, 4-dioxane (2 mL) was added thereto with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1 mL), DIPEA (80mg, 0.617mmol) and acrylonitrile (20mg, 0.369mmol) were sequentially added thereto, and the resulting reaction mixture was further stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was preliminarily isolated and purified by silica gel chromatography and further isolated and purified by preparative TLC to give the title compound as a gray solid (12mg, 20%).
1 H NMR(400MHz，CD 3 OD)δ8.06(d，J＝9.3Hz，1H)，7.08(d，J＝9.4Hz，1H)，6.68(s，1H)，6.49(s，1H)，4.46-4.28(m，1H)，3.97-3.73(m，4H)，3.52-3.36(m，6H)，2.73(t，J＝6.7Hz，2H)，2.62(t，J＝6.7Hz，2H)，2.34(s，3H)，2.11-1.61(m，8H).
MS m/z(ESI):488.2[M+H] + .
Example 192
3- ((3-exo) -3- ((7- (3-methoxyazetidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002531
Preparation of 3- ((3-exo) -3- ((7- (3-methoxyazetidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):488.3[M+H] + .
Example 193
3- ((3-exo) -3- ((7- (4-methoxypiperidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002532
Preparation of 3- ((3-exo) -3- ((7- (4-methoxypiperidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):516.3[M+H] + .
Example 194
3- ((3-exo) -3- ((7- (4- (dimethylamino) piperidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002541
Preparation of 3- ((3-exo) -3- ((7- (4- (dimethylamino) piperidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):529.3[M+H] + .
Example 195
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyrrolidin-1-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002542
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyrrolidin-1-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):472.3[M+H] + .
Example 196
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (methylamino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002551
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (methylamino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):432.3[M+H] + .
Example 197
3- ((3-exo) -3- ((7- (methyl (oxetan-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002552
Preparation of 3- ((3-exo) -3- ((7- (methyl (oxetan-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):502.3[M+H] + .
Example 198
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylazetidin-3-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002561
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylazetidin-3-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):501.3[M+H] + .
Example 199
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002562
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):516.3[M+H] + .
Example 200
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylpiperidin-4-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002571
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylpiperidin-4-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):529.3[M+H] + .
Example 201
3- ((3-exo) -3- ((7- (methyl (pyridin-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002572
Preparation of 3- ((3-exo) -3- ((7- (methyl (pyridin-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
MS m/z(ESI):523.3[M+H] + .
Example 202
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002581
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 191.
MS m/z(ESI):502.3[M+H] + .
Example 203
3- ((3-exo) -3- ((7- (1H-imidazol-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002582
Preparation of 3- ((3-exo) -3- ((7- (1H-imidazol-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 191.
1 H NMR(400MHz，CD 3 OD)δ8.29(s，1H)，8.21(d，J＝8.9Hz，1H)，7.70(s，1H)，7.64-7.26(m，2H)，7.19(s，1H)，6.62(s，0.8H)，5.93(s，0.2H)，4.47-4.22(m，1H)，3.41-3.36(m，2H)，2.76(t，J＝6.9Hz，2H)，2.63(t，J＝6.9Hz，2H)，2.33(s，3H)，2.08-2.01(m，2H)，2.00-1.79(m，4H)，1.74-1.63(m，2H).
MS m/z(ESI):469.2[M+H] + .
Example 204
3- ((3-exo) -3- ((7- (2-methoxyethoxy) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002591
Preparation of 3- ((3-exo) -3- ((7- (2-methoxyethoxy) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
MS m/z(ESI):477.3[M+H] + .
Example 205
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-ylmethoxy) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002592
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-ylmethoxy) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 169.
MS m/z(ESI):503.3[M+H] + .
Example 206
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) methoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002593
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) methoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
MS m/z(ESI):502.3[M+H] + .
Example 207
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-ylmethoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002601
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyridin-3-ylmethoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
MS m/z(ESI):510.3[M+H] + .
Example 208
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002602
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 169.
MS m/z(ESI):488.3[M+H] + .
Example 209
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylpiperidin-4-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002611
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylpiperidin-4-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 169.
MS m/z(ESI):516.3[M+H] + .
Example 210
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (morpholinomethyl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002612
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (morpholinomethyl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 169.
MS m/z(ESI):516.3[M+H] + .
Example 211
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methylazetidin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002621
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methylazetidin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 169.
MS m/z(ESI):486.3[M+H] + .
Example 212
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002622
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 169.
MS m/z(ESI):473.3[M+H] + .
Example 213
1- (((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002631
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic compound (10 mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 3-cyanoazetidine-1-sulfonyl chloride (44mg, 0.244mmol) were added successively, and the reaction mixture was stirred at 0 ℃ for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (59.3mg, 54%).
1 H NMR(400MHz，CD 3 OD)δ8.12(s，1H)，7.50(s，1H)，7.29(d，J＝44.1Hz，1H)，7.06(s，1H)，6.58(s，1H)，4.36(s，1H)，4.12(s，2H)，4.03(t，J＝8.4Hz，2H)，3.90(t，J＝7.0Hz，2H)，3.69-3.57(m，1H)，2.20(s，3H)，2.10-1.51(m，8H).
MS m/z(ESI):494.2[M+H] + .
Example 214
1- (((3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002632
Tert-butyl (3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (174mg, 0.36mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (20 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (1.19mL, 7.2 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (78mg, 0.432mmol) were added in this order, and the reaction mixture was stirred at 0 ℃ for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase HPLC to give the title compound (17.7mg, 9%).
1 H NMR(400MHz，MeOD-d 4 )δ8.02(s，1H)，7.42(s，1H)，7.20(s，1H)，6.57(s，1H)，4.51-4.40(m，1H)，4.27(s，2H)，4.17(t，J＝8.5Hz，2H)，4.13-4.05(m，2H)，3.64-3.53(m，1H)，2.34(s，3H)，2.16(s，4H)，1.98(d，J＝42.2Hz，2H)，1.76(t，J＝11.9Hz，2H).
MS m/z(ESI):528.2[M+H] + .
Example 215
1- (((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002641
Preparation of 1- (((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 213.
1 H NMR(400MHz，CD 3 OD)δ8.11(dd，J＝9.1，6.1Hz，1H)，7.21-6.82(m，2H)，6.56(s，0.8H)，5.88(s，0.2H)，4.58-4.34(m，1H)，4.29-4.19(m，2H)，4.17-4.08(m，2H)，4.06-3.96(m，2H)，3.72-3.58(m，1H)，2.31(s，3H)，2.18-1.85(m，6H)，1.82-1.66(m，2H).
MS m/z(ESI):512.1[M+H] + .
Example 216
1- (((3-exo) -3- ((7-cyclopropyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002651
Preparation of 1- (((3-exo) -3- ((7-cyclopropyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 213.
1 H NMR(400MHz，CD 3 OD)δ8.04(s，1H)，7.26-6.93(m，2H)，6.50(s，1H)，4.58-4.37(m，1H)，4.31-4.18(m，2H)，4.18-4.07(m，2H)，4.06-3.95(m，2H)，3.71-3.58(m，1H)，2.32(s，3H)，2.17-1.71(m，8H)，1.34-1.25(m，1H)，1.19-1.03(m，2H)，0.94-0.75(m，2H).
MS m/z(ESI):534.1[M+H] + .
Example 217
3- ((3-exo) -3- (((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002652
The first step is as follows: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002653
To a solution of 2-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) quinazolin-4-amine (200mg, 0.77mmol) in N-butanol (10 mL) was added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (222mg, 0.92mmol), DIPEA (199mg, 1.54mmol) in this order, followed by stirring at 170 ℃ for 4 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a white solid (275mg, 77%).
MS m/z(ESI):464.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- (((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002661
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL) of hydrochloric acid, and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10 mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was continued at room temperature for 10 minutes, and after the addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (30.5mg, 29%).
1 H NMR(400MHz，DMSO)δ＝12.09(s，1H)，10.04(s，1H)，8.24(s，1H)，7.45(s，1H)，7.33-6.42(m，4H)，4.79(s，1H)，4.01-3.79(m，6H)，3.74-3.67(m，1H)，2.15(s，3H)，2.09-1.57(m，10H).
MS m/z(ESI):508.2[M+H] + .
Example 218
1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002671
The first step of reaction: preparation of 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0002321528230002672
2, 4-dichloro-7-methoxyquinazoline (497mg, 2.17mmol), 5-methyl-1H-pyrazol-3-amine (221mg, 2.28mmol) and DIPEA (0.75mL, 4.56mmol) were added to absolute ethanol (10 mL), stirred at room temperature for 24 hours, and then heated to 50 ℃ to react for 5 hours. The solvent was removed by concentration under reduced pressure, the residue was washed with a mixed solvent of ethanol-water (v/v =1, 20 mL), and the residue was dried under reduced pressure to give the title compound (509mg, 81%).
MS m/z(ESI):290.0[M+H] + .
The second step of reaction: preparation of tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002673
2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (150mg, 0.518mmol), tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (249mg, 1.036mmol) and DIPEA (0.43mL, 2.59mmol) were added to N-butanol (3 mL) and heated to 170 ℃ with a microwave synthesizer for 6 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase column chromatography to give the title compound (193mg, 75%).
MS m/z(ESI):494.2[M+H] + .
The third step of reaction: preparation of 1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002681
Tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (193mg, 0.39mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic compound (20 mL), the reaction was stirred at room temperature for 60 minutes, the solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10 mL), the reaction mixture was cooled to 0 ℃ and DIPEA (1.93mL, 11.7 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (71mg, 0.39mmol) were added in this order, and the reaction mixture was stirred at 0 ℃ for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (97mg, 46%).
1 H NMR(400MHz，DMSO-d 6 )δ12.11(s，1H)，9.77(s，1H)，8.23(d，J＝8.9Hz，1H)，6.72(s，1H)，6.67(d，J＝8.8Hz，1H)，6.48(s，1H)，5.40-5.25(m，1H)，4.18(s，2H)，4.06(t，J＝8.6Hz，2H)，4.01-3.92(m，2H)，3.87-3.74(m，4H)，2.96(s，3H)，2.23(s，3H)，2.06-1.89(m，4H)，1.83(d，J＝5.8Hz，2H)，1.61(d，J＝11.2Hz，2H).
MS m/z(ESI):538.2[M+H] + .
Example 219
1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002682
The first step of reaction: tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002691
2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (50mg, 0.173mmol) and tert-butyl (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate oxalate (171mg, 0.518mmol) were added to N-butanol (10 mL), heated to 170 ℃ by a microwave synthesizer for 8 hours, concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to give the title compound (68mg, 80%).
MS m/z(ESI):494.2[M+H] + .
The second step of reaction: 1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002692
Tert-butyl (3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (68mg, 0.138mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic ring (15 mL) and the reaction stirred at room temperature for 60 minutes. The solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.68mL, 4.14mmol) and 3-cyanoazetidine-1-sulfonyl chloride (25mg, 0.138mmol) were added successively, and the reaction mixture was further stirred at 0 ℃ for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (6.9mg, 9%).
1 H NMR(400MHz，DMSO-d 6 )δ12.10(s，1H)，9.83(s，1H)，8.24(d，J＝7.3Hz，1H)，6.65(dd，J＝29.7，20.4Hz，4H)，4.83(s，1H)，4.02(t，J＝8.5Hz，2H)，3.92(dd，J＝14.9，8.4Hz，4H)，3.87-3.73(m，4H)，2.21(s，3H)，2.04(d，J＝4.3Hz，3H)，1.92-1.68(m，7H).
MS m/z(ESI):538.2[M+H] + .
Example 220
1- (((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002701
Preparation of 1- (((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrido [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 213.
1 H NMR(400MHz，DMSO-d 6 )δ12.61-12.05(m，1H)，10.86(s，0.2H)，9.45-9.08(m，0.8H)，8.40(s，1H)，7.82-7.49(m，2H)，7.20-6.96(m，1H)，6.93-6.59(m，0.8H)，6.08(s，0.2H)，4.47-4.27(m，1H)，4.22-4.11(m，2H)，4.10-4.01(m，2H)，3.99-3.88(m，2H)，3.87-3.74(m，1H)，2.26(s，3H)，2.14-1.79(m，6H)，1.76-1.57(m，2H).
MS m/z(ESI):495.1[M+H] + .
Example 221
1- (((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002702
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002703
2, 4-dichloroquinazoline (398mg, 2.0mmol), 5-methylthiooxazol-2-amine (251mg, 2.2mmol) and DIPEA (1mL, 6.0mmol) were dispersed in absolute ethanol (10 mL), and the resulting reaction mixture was heated to 70 ℃ and stirred for reaction for 24 hours, cooled to room temperature, filtered, and the resulting yellow solid was washed with a small amount of absolute ethanol and air-dried. The above crude product was dispersed in n-butanol (10 mL), t-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (452mg, 2.0 mmol) and DIPEA (0.33mL, 2.0 mmol) were added, stirred and mixed well at room temperature, transferred to a microwave synthesizer and heated at 170 ℃ for reaction for 3 hours, concentrated under reduced pressure to remove the solvent, and the crude product was isolated by silica gel column chromatography to give the title compound as a pale yellow solid (45mg, 5%).
MS m/z(ESI):467.1[M+H] + .
The second step is that: preparation of 1- (((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002711
Tert-butyl (3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (45mg, 0.097 mmol) was dissolved in 4M HCl 1, 4-epoxyhexacyclic compound (15 mL), the reaction was stirred at room temperature for 60 minutes, the solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (5 mL), cooled to 0 deg.C, DIPEA (0.32mL, 1.94mmol) and 3-cyanoazetidine-1-sulfonyl chloride (19mg, 0.106mmol) were added in succession, and the reaction mixture was stirred at 0 deg.C for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound as a pale yellow solid compound (12.4 mg, 25%).
1 H NMR(400MHz，CD 3 OD:CDCl 3 ，v/v＝1:2)δ8.30(d，J＝4.5Hz，1H)，7.71-7.65(m，1H)，7.39-7.27(m，2H)，7.17(s，1H)，4.86-4.79(m，1H)，4.32(s，2H)，4.19(t，J＝8.5Hz，2H)，4.11-4.04(m，2H)，3.62(ddd，J＝15.1，8.5，6.1Hz，1H)，2.45(s，3H)，2.32-2.16(m，4H)，2.09(d，J＝7.6Hz，2H)，1.93-1.84(m，2H).
MS m/z(ESI):511.1[M+H] + .
Example 222
1- (((3-exo) -3- ((7-chloro-4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002721
Preparation of 1- (((3-exo) -3- ((7-chloro-4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 221.
MS m/z(ESI):545.1[M+H] + .
Example 223
1- (((3-exo) -3- ((7-methoxy-4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002722
Preparation of 1- (((3-exo) -3- ((7-methoxy-4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 221.
MS m/z(ESI):541.2[M+H] + .
Example 224
Figure BDA0002321528230002723
Tert-butyl (3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was dispersed in dichloromethane (2 mL), a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (20 mL) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was dried under reduced pressure on an oil pump for 10 minutes. The crude product was dissolved in anhydrous N, N-dimethylformamide (8 mL), cooled to 0 ℃ in an ice-water bath, DIPEA (1.2mL, 7.1mmol), dimethylglycine (0.31mL, 4.72mmol) and HATU (118mg, 0.31mmol) were added sequentially with stirring, and the resulting reaction mixture was stirred at 0 ℃ for 60 minutes. The solvent was removed by concentration under reduced pressure and the crude product was isolated by prep-HPLC to give the title compound as a white solid (20.7 mg, 21%).
1 H NMR(400MHz，DMSO-d 6 )δ10.12(s，1H)，8.33(s，1H)，7.31(s，1H)，7.17(s，1H)，7.13-6.86(m，2H)，6.60(s，1H)，4.52(s，1H)，4.42(d，J＝3.4Hz，2H)，3.16(s，2H)，2.38-2.12(m，9H)，2.05-1.94(m，2H)，1.93-1.73(m，4H)，1.63-1.46(m，2H).
MS m/z(ESI):469.1[M+H] + .
Example 225
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002731
Preparation of 2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one reference example 224.
1 H NMR(400MHz，DMSO-d 6 )δ12.21(s，1H)，10.13(s，1H)，8.33(s，1H)，7.54(t，J＝7.5Hz，1H)，7.27(d，J＝30.8Hz，1H)，7.08(s，1H)，6.78(s，1H)，6.61(s，1H)，4.56(d，J＝6.1Hz，1H)，4.48(s，1H)，4.32(d，J＝5.3Hz，1H)，3.65(dd，J＝32.9，14.8Hz，2H)，2.53(s，6H)，2.25(s，3H)，1.94(ddd，J＝36.8，20.0，10.6Hz，6H)，1.56(dd，J＝19.2，9.5Hz，2H).
MS m/z(ESI):435.2[M+H] + .
Example 226
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230002741
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-2-yl) methanone reference example 224.
1 H NMR(400MHz，DMSO-d 6 )δ12.29(s，1H)，10.80(s，1H)，10.33(s，1H)，8.61(d，J＝4.3Hz，1H)，8.52-8.24(m，1H)，7.96(td，J＝7.8，1.7Hz，1H)，7.73(d，J＝7.8Hz，1H)，7.71-7.57(m，1H)，7.52(ddd，J＝7.5，4.9，1.0Hz，1H)，7.39(d，J＝18.4Hz，1H)，7.21(d，J＝39.2Hz，1H)，6.60(s，1H)，4.74(s，1H)，4.69-4.44(m，2H)，2.27(s，3H)，2.12-1.69(m，8H).
MS m/z(ESI):455.2[M+H] + .
Example 227
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-3-yl) methanone
Figure BDA0002321528230002742
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-3-yl) methanone reference example 224.
1 H NMR(400MHz，DMSO-d 6 )δ12.25(s，1H)，10.36(s，1H)，10.05(s，1H)，8.78-8.62(m，2H)，8.34(d，J＝29.6Hz，1H)，7.90(d，J＝7.0Hz，1H)，7.62-7.48(m，2H)，7.31(dd，J＝19.3，8.1Hz，1H)，7.12(s，1H)，6.60(s，1H)，4.68(d，J＝4.8Hz，1H)，4.53(d，J＝9.2Hz，1H)，4.02(d，J＝3.1Hz，1H)，2.25(s，3H)，2.16-1.48(m，8H).
MS m/z(ESI):455.2[M+H] + .
Example 228
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-4-yl) methanone
Figure BDA0002321528230002751
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-4-yl) methanone reference example 224.
1 H NMR(400MHz，DMSO-d 6 )δ12.23(s，1H)，10.21(s，1H)，8.70(d，J＝5.5Hz，2H)，8.32(dd，J＝28.3，8.1Hz，1H)，7.59-7.51(m，1H)，7.45(d，J＝1.8Hz，2H)，7.36-7.22(m，1H)，7.09(t，J＝7.4Hz，1H)，6.86(s，1H)，6.59(s，1H)，4.67(d，J＝4.9Hz，1H)，4.61-4.44(m，1H)，3.94(d，J＝1.9Hz，1H)，2.24(s，3H)，2.09-1.53(m，8H).
MS m/z(ESI):455.2[M+H] + .
Example 229
1- ((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one
Figure BDA0002321528230002752
Preparation of 1- ((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one reference example 224.
MS m/z(ESI):494.2[M+H] + .
Example 230
2- (methylamino) -1- ((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ethan-1-one
Figure BDA0002321528230002761
Preparation of 2- (methylamino) -1- ((3-exo) -3- ((4- ((5-methylthiooxazol-2-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ethan-1-one reference example 224.
MS m/z(ESI):452.2[M+H] + .
Example 231
2, 2-difluoro-1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002762
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (10 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 deg.C, DIPEA (0.73mL, 4.44mmol) was added, and after mixing well, a mixture of difluoroacetic acid (0.023mL, 0.233mmol) and HATU (1699 mg, 4.44mmol) previously dissolved in 1mL dry N, N-dimethylformamide was added and reacted for 10 minutes, and the reaction mixture was stirred at 0 deg.C for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (48.9mg, 52%).
1 H NMR(400MHz，MeOD-d 4 )δ7.99(d，J＝7.7Hz，1H)，7.56-7.44(m，1H)，7.40-7.19(m，1H)，7.13-7.03(m，1H)，6.55(d，J＝4.7Hz，1H)，6.33(t，J＝53.6Hz，1H)，4.57(s，2H)，4.46-4.40(m，1H)，2.18(d，J＝33.6Hz，3H)，2.09-1.75(m，6H)，1.56(t，J＝12.1Hz，2H).
MS m/z(ESI):428.1[M+H] + .
Example 232
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-3-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) quinazoline-2, 4-diamine
Figure BDA0002321528230002771
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (10 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 3-pyridinesulfonyl chloride hydrochloride (50mg, 0.233mmol) were added in this order, and the reaction mixture was stirred at 0 ℃ for 0.5 hour. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase HPLC to give the title compound (20.5mg, 19%).
1 H NMR(400MHz，DMSO-d 6 )δ8.98(d，J＝2.0Hz，1H)，8.76(dd，J＝4.8，1.4Hz，1H)，8.27-8.19(m，1H)，8.14-8.01(m，1H)，7.60-7.44(m，2H)，7.29(ddd，J＝15.0，9.9，4.2Hz，1H)，7.07(t，J＝7.4Hz，1H)，6.58-6.39(m，1H)，4.30(dd，J＝6.0，2.6Hz，3H)，2.17(s，3H)，2.08-1.95(m，2H)，1.74(dd，J＝16.7，6.2Hz，2H)，1.64(dd，J＝17.3，6.7Hz，2H)，1.43-1.32(m，2H).
MS m/z(ESI):491.1[M+H] + .
Example 233
N2- ((3-exo) -8- ((2-methoxyethyl) sulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) quinazoline-2, 4-diamine
Figure BDA0002321528230002772
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic compound (10 mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 2-methoxyethane-1-sulfonyl chloride (37mg, 0.233mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase HPLC to give the title compound (25.1mg, 43%).
1 H NMR(400MHz，DMSO-d 6 )δ8.31(s，1H)，7.64(s，1H)，7.41(s，1H)，7.24(dd，J＝23.8，8.5Hz，1H)，6.61(s，1H)，4.49-4.43(m，1H)，4.26(s，2H)，3.76(t，J＝6.2Hz，2H)，3.43-3.29(m，5H)，2.32(s，3H)，2.11-1.86(m，6H)，1.74(t，J＝13.5Hz，2H).
MS m/z(ESI):472.2[M+H] + .
Example 234
N2- ((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] octan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) quinazoline-2, 4-diamine
Figure BDA0002321528230002781
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (10 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (5 mL), anhydrous potassium carbonate (184mg, 1.33mmol) and 1-bromo-2-fluoroethane (50mg, 0.233mmol) were successively added, and the reaction mixture was stirred at 40 ℃ for 19 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (27.3mg, 31%).
1 H NMR(400MHz，DMSO-d 6 )δ8.15(d，J＝17.8Hz，1H)，7.56(s，1H)，7.35(d，J＝44.5Hz，1H)，7.11(s，1H)，6.71(s，1H)，4.64-4.45(m，2H)，4.33-4.19(m，1H)，3.35(s，2H)，2.91-2.68(m，2H)，2.32(s，3H)，2.11-1.56(m，8H).
MS m/z(ESI):396.2[M+H] + .
Example 235
3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002791
The first step is as follows: preparation of (3- ((2, 7-dichloroquinazolin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0002321528230002792
2,4, 7-trichloroquinazoline (300mg, 1.29mmol), (3-amino-1H-pyrazol-5-yl) methanol (180mg, 1.55mmol), and DIPEA (500mg, 3.87mmol) were added to 1, 4-dioxane (5 mL), and the mixture was uniformly mixed and reacted at room temperature overnight. Concentrated under reduced pressure, and the resulting crude was combined with methanol (5 mL), filtered, and the solid dried to give the title compound as a white solid (350mg, 87%)
MS m/z(ESI):310.0[M+H] + .
The second step: preparation of tert-butyl (3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002793
(3- ((2, 7-dichloroquinazolin-4-yl) amino) -1H-pyrazol-5-yl) methanol (150mg, 0.49mmol), tert-butyl (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (150mg, 0.58mmol) and DIPEA (190mg, 1.47mmol) were added to n-butanol (2 mL), mixed well, reacted at microwave 150 ℃ for 10 hours, cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the desired product as a white solid (140mg, 55%).
MS m/z(ESI):528.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230002801
To a solution of tert-butyl (3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (140mg, 0.27mmol) in methanol (10 mL) was slowly added dioxane hydrochloride (4N, 2 mL) dropwise, the reaction was carried out at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the resulting crude product was dissolved in methanol (15 mL), and DIPEA (0.5 mL), acrylonitrile (25mg, 0.46mmol) and the reaction were added at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and isolated and purified by prep-HPLC to give the title compound as a white solid (22mg, 20%).
1 H NMR(400MHz，DMSO-d 6 )δ12.41(s，1H)，10.02(s，1H)，8.35(d，J＝8.4Hz，1H)，7.28(s，1H)，7.06(d，J＝8.4Hz，1H)，6.52-6.54(m，1H)，5.53-5.55(m，1H)，5.25(s，1H)，4.46(t，J＝5.2Hz，2H)，3.31-2.87(m，7H)，2.66-2.59(m，2H)，2.08-1.87(m，5H)，1.60-1.41(m，5H).
MS m/z(ESI):481.2[M+H] + .
Example 236
3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230002802
Preparation of 3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 235.
H NMR(400MHz，DMSO-d 6 )δ12.45(s，1H)，10.08(d，J＝8.8Hz，1H)，8.36(d，J＝8.8Hz，1H)，7.29(s，1H)，7.07(d，J＝8.8Hz，1H)，6.62-6.54(m，1H)，5.27-5.11(m，2H)，4.50(d，J＝5.6Hz，2H)，3.31-2.27(m，2H)，2.94(d，J＝16.0Hz，3H)，2.67-2.58(m，4H)，1.92-1.81(m，4H)，1.71-1.62(m，2H)，1.39-1.23(m，2H).
MS m/z(ESI):467.2[M+H] + .
Example 237
1- (((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002811
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (200mg, 0.439mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (20 mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (1.45mL, 8.78mmol) and 3-cyanoazetidine-1-sulfonyl chloride (95mg, 0.527mmol) were added successively, and the reaction mixture was stirred at 0 ℃ for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase HPLC to give the title compound (70mg, 32%).
1 H NMR(400MHz，MeOD-d 4 )δ7.37(d，J＝6.0Hz，1H)，6.94(d，J＝6.0Hz，1H)，6.25(s，1H)，4.44-4.34(m，1H)，4.26(s，2H)，4.16(t，J＝8.5Hz，2H)，4.12-4.05(m，2H)，3.57(ddd，J＝15.3，8.7，6.5Hz，1H)，2.31(s，3H)，2.23-2.10(m，4H)，2.01(d，J＝7.4Hz，2H)，1.73(dd，J＝18.2，7.1Hz，2H).
MS m/z(ESI):500.1[M+H] + .
Example 238
3- ((3-exo) -3- (((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino)) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002821
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, it was dissolved in N, N-dimethylformamide (10 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, and stirred at room temperature for 10 minutes, and after adding 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring at room temperature was continued overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (14.4 mg, 13%).
1 H NMR(400MHz，DMSO)δ＝12.02(s，1H)，9.81(s，1H)，7.61(s，1H)，6.90(s，1H)，6.59(d，J＝57.6Hz，2H)，4.74(s，1H)，3.96(t，J＝8.4Hz，2H)，3.85(dd，J＝16.8Hz，6.4，4H)，3.75-3.67(m，1H)，2.14(s，3H)，2.00(d，J＝8.4Hz，2H)，1.87-1.60(m，8H).
MS m/z(ESI):514.1[M+H] + .
Example 239
1- (((3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002831
The first step is as follows: preparation of tert-butyl- (3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230002832
To a solution of 2-chloro-N- (5-methyl-1 h-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (250mg, 0.94mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (287 mg,1.1 3mmol), DIPEA (242mg, 1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale white solid (228mg, 50%).
MS m/z(ESI):484.2[M+H] + .
The second step: preparation of 1- (((3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002833
Tert-butyl- (3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10 mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was continued at room temperature for 10 minutes, and after the addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a white solid (46.0 mg, 42%).
1 H NMR(400MHz，DMSO)δ＝12.09(s，1H)，9.79(s，1H)，7.68(d，J＝6.0Hz，1H)，7.02(d，J＝6.0Hz，1H)，6.43(s，1H)，5.77(s，1H)，3.98(dt，J＝14.4，8.4Hz，6H)，3.84-3.74(m，1H)，2.90(s，3H)，2.22(s，3H)，2.13-1.61(m，10H).
MS m/z(ESI):528.2[M+H] + .
Example 240
1- (((3-exo) -3- (methyl (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002841
The first step of reaction: preparation of tert-butyl (3-exo) -3- (methyl (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002842
2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (150mg, 0.536 mmol) and tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (257mg, 1.072mmol) were added to N-butanol (10 mL) and heated to 170 ℃ with a microwave synthesizer for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in methylene chloride, washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by silica gel column chromatography to give the title compound (73mg, 28%).
MS m/z(ESI):484.2[M+H] + .
The second step of reaction: preparation of 1- (((3-exo) -3- (methyl (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002851
Tert-butyl (3-exo) -3- (methyl (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (73mg, 0.151mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic ring (20 mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.75mL, 4.53mmol) and 3-cyanoazetidine-1-sulfonyl chloride (30mg, 0.166mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 4.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (31.5mg, 40%).
1 H NMR(400MHz，DMSO-d 6 )δ12.06(s，1H)，9.66(s，1H)，7.35(s，1H)，6.48(s，1H)，5.31-5.15(m，1H)，4.18(d，J＝1.0Hz，2H)，4.06(t，J＝8.6Hz，2H)，4.00-3.91(m，2H)，3.80(ddd，J＝12.8，8.9，6.5Hz，1H)，2.90(s，3H)，2.40(s，3H)，2.22(s，3H)，2.07-1.99(m，2H)，1.95(dd，J＝18.2，7.0Hz，2H)，1.88-1.79(m，2H)，1.62(dd，J＝11.8，4.1Hz，2H).
MS m/z(ESI):528.2[M+H] + .
Example 241
1- (((3-exo) -3- (methyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002852
The first step of reaction: preparation of tert-butyl (3-exo) -3- (methyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230002861
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376 mmol) and tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (181mg, 0.752mmol) were added to N-butanol (3 mL), and heated to 170 ℃ with a microwave synthesizer for 18 hours. The solvent was removed by concentration under reduced pressure, and the residue was used directly in the next reaction.
MS m/z(ESI):470.2[M+H] + .
The second step of reaction: preparation of 1- (((3-exo) -3- (methyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230002862
Tert-butyl (3-exo) -3- (methyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate was dissolved in 4M HCl 1, 4-epoxyhexacyclic compound (20 mL), the reaction was stirred at room temperature for 30 minutes, the solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase column chromatography to give 117mg of a white solid.
The above white solid was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 ℃ and DIPEA (0.14mL, 0.632mmol) and 3-cyanoazetidine-1-sulfonyl chloride (57mg, 0.316 mmol) were added in this order, and the reaction mixture was stirred at 0 ℃ for 17 hours. The solvent was removed by concentration under reduced pressure and the residue was isolated by prep-HPLC to give the title compound (16.4mg, 10%).
1 H NMR(400MHz，MeOD-d 4 )δ7.37(d，J＝5.9Hz，1H)，6.98(d，J＝5.7Hz，1H)，6.40(s，1H)，5.40-5.28(m，1H)，4.31-4.24(m，2H)，4.17(t，J＝8.5Hz，2H)，4.11-4.04(m，2H)，3.57(ddd，J＝15.4，8.9，6.7Hz，1H)，3.04(s，3H)，2.31(s，3H)，2.17(dd，J＝8.6，3.3Hz，2H)，2.11-2.01(m，2H)，2.00-1.92(m，2H)，1.75(ddd，J＝10.8，4.3，2.7Hz，2H).
MS m/z(ESI):514.1[M+H] + .
Example 242
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ethan-1-one
Figure BDA0002321528230002871
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.32mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and dimethylglycine (24mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (17.1mg, 18%).
1 H NMR(400MHz，DMSO)δ＝12.00(s，1H)，9.80(s，1H)，7.61(s，1H)，6.98-6.45(m，3H)，4.76(s，1H)，4.59(s，1H)，4.27(s，1H)，3.30(s，6H)，3.05(s，2H)，2.16(s，3H)，2.14(s，2H)，2.07-1.92(m，2H)，1.86-1.40(m，6H).
MS m/z(ESI):455.2[M+H] + .
Example 243
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002881
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (46mg, 0.36mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes in an ice-water bath, and dimethylglycine (10mg, 0.1mmol) was added and then stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (4.4 mg, 11%).
1 H NMR(400MHz，DMSO)δ＝12.08(s，1H)，9.88(s，1H)，7.65(s，1H)，7.11-6.46(m，3H)，4.47(d，J＝30.0Hz，3H)，3.06(s，2H)，2.21(s，9H)，2.04-1.66(m，6H)，1.62-1.44(m，2H).
MS m/z(ESI):441.2[M+H] + .
Example 244
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one
Figure BDA0002321528230002882
Figure BDA0002321528230002891
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (46mg, 0.36mmol) was slowly added dropwise, and stirring was carried out for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (14.5mg, 0.1mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (7.8mg, 18%).
1 H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.88(s，1H)，7.66(s，1H)，7.11-6.49(m，3H)，4.48(d，J＝26.4Hz，3H)，3.60(s，4H)，3.17(s，2H)，2.46(s，4H)，2.23(s，3H)，1.98(s，2H)，1.90-1.45(m，6H).
MS m/z(ESI):483.2[M+H] + .
Example 245
1- ((3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one
Figure BDA0002321528230002892
Preparation of 1- ((3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one reference example 244.
1 H NMR(400MHz,DMSO-d 6 )δ＝9.85(s,1H),8.22(s,1H),7.68(d,J＝6.0Hz,1H),7.02(d,J＝6.0Hz,1H),6.53(s,1H),5.37(s,1H),4.54(d,J＝16.4Hz,2H),3.58(d,J＝4.0Hz,4H),3.04(d,J＝13.2Hz,2H),2.85(s,3H),2.45(s,4H),2.23(s,3H),2.03-1.97(m,2H),1.87-1.59(m,6H).
MS m/z(ESI):497.2[M+H] + .
Example 246
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-morpholinoethane-1-one
Figure BDA0002321528230002901
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (33mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (18.0 mg, 17%).
1 H NMR(400MHz，DMSO)δ＝12.08(s，1H)，9.87(s，1H)，7.68(s，1H)，7.07-6.53(m，3H)，4.83(s，1H)，4.65(s，1H)，4.37(s，1H)，3.59(d，J＝4.0Hz，4H)，3.12(dd，J＝25.2，12.4Hz，2H)，2.39(s，4H)，2.21(s，3H)，2.11-1.51(m，10H).
MS m/z(ESI):497.2[M+H] + .
Example 247
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethan-1-one
Figure BDA0002321528230002911
The first step is as follows: preparation of tert-butylmethyl (2- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-carbonylethyl) carbamate
Figure BDA0002321528230002912
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (200mg, 0.42mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 10mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (240mg, 0.64mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (216mg, 1.68mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after N- (t-butoxycarbonyl) -N-methylglycine (87mg, 0.46mmol) was added. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a white solid (205mg, 90%).
MS m/z(ESI):541.2[M+H] + .
The second step: preparation of 1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethan-1-one
Figure BDA0002321528230002913
Tert-butylmethyl (2- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-carbonylethyl) carbamate (205mg, 0.38mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 10mL) and after stirring at room temperature for 30 minutes, aqueous ammonia (10 mL) was added dropwise to the reaction liquid in an ice-water bath, and then the reaction liquid was concentrated under reduced pressure to obtain the product by prep-HPLC to give the title compound as a white solid (37.6mg, 22%).
1 H NMR(400MHz，DMSO)δ＝12.10(s，1H)，9.88(s，1H)，7.68(s，1H)，6.96(s，1H)，6.61(s，2H)，4.84(s，1H)，4.69(s，1H)，4.12(s，1H)，2.29(s，3H)，2.20(s，3H)，2.15-1.96(m，3H)，1.87-1.47(m，10H).
MS m/z(ESI):441.2[M+H] + .
Example 248
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone
Figure BDA0002321528230002921
Preparation of ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone reference example 247.
1 H NMR(400MHz，DMSO-d 6 )δ＝12.08(s，1H)，9.89(s，1H)，7.66(s，1H)，7.06-6.51(m，3H)，4.55-4.35(m，3H)，3.73(s，1H)，3.01(s，1H)，2.64(d，J＝6.8Hz，2H)，2.23(s，3H)，2.10-1.43(m，12H).
MS m/z(ESI):453.1[M+H] + .
Example 249
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((S) -pyrrolidin-2-yl) methanone
Figure BDA0002321528230002922
Preparation of ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((S) -pyrrolidin-2-yl) methanone reference example 247.
1 H NMR(400MHz，DMSO-d 6 )δ＝12.11(s，1H)，9.90(s，1H)，7.67(s，1H)，5.98-6.54(m，3H)，4.58-4.35(m，3H)，4.09-4.02(m，1H)，3.11(s，1H)，2.97-2.64(m，2H)，2.23(s，3H)，2.10-1.37(m，10H).
MS m/z(ESI):453.1[M+H] + .
Example 250
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -morpholin-3-yl) methanone
Figure BDA0002321528230002931
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -morpholin-3-yl) methanone reference example 247.
MS m/z(ESI):483.2[M+H] + .
Example 251
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone
Figure BDA0002321528230002932
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone reference example 247.
MS m/z(ESI):467.2[M+H] + .
Example 252
2- ((2-methoxyethyl) amino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ethan-1-one
Figure BDA0002321528230002941
Preparation of 2- ((2-methoxyethyl) amino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ethan-1-one is according to example 247.
MS m/z(ESI):485.2[M+H] + .
Example 253
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- ((pyridin-3-ylmethyl) amino) ethan-1-one
Figure BDA0002321528230002942
Preparation of 1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- ((pyridin-3-ylmethyl) amino) ethan-1-one is referred to example 247.
MS m/z(ESI):518.2[M+H] + .
Example 254
2- ((4-methoxybenzyl) amino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002943
Preparation of 2- ((4-methoxybenzyl) amino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one is according to example 247.
MS m/z(ESI):533.2[M+H] + .
Example 255
2- (ethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002951
Preparation of 2- (ethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one reference example 247.
MS m/z(ESI):441.2[M+H] + .
Example 256
2- (cyclopropylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230002952
Preparation of 2- (cyclopropylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one reference example 247.
MS m/z(ESI):453.2[M+H] + .
Example 257
1- ((3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Figure BDA0002321528230002961
Tert-butyl- (3-exo) -3- (methyl (4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5 mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and 2- (4-methylpiperazin-1-yl) acetic acid (36mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (43.8mg, 40%).
1 H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.79(s，1H)，7.68(d，J＝6.0Hz，1H)，7.02(d，J＝6.0Hz，1H)，6.46(s，1H)，5.81(s，1H)，4.71(s，1H)，4.39(s，1H)，3.22(d，J＝12.8Hz，1H)，3.06(d，J＝12.8Hz，1H)，2.85(s，3H)，2.40(s，8H)，2.22(s，3H)，2.17(s，3H)，2.12-2.02(m 2H)，1.90-1.61(m，8H).
MS m/z(ESI):424.2[M+H] + .
Example 258
1- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Figure BDA0002321528230002962
Figure BDA0002321528230002971
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and 2- (4-methylpiperazin-1-yl) acetic acid (36mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (25.2mg, 24%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.07(s，1H)，9.92(s，1H)，7.68(s，1H)，6.96-6.61(m，3H)，4.85(s，1H)，4.65(s，1H)，4.37(s，1H)，3.10(s，2H)，2.37(s，8H)，2.21(s，3H)，2.14(s，3H)，2.09-1.99(m，2H)，1.97-1.46(m，8H).
MS m/z(ESI):510.2[M+H] + .
Example 259
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (piperazin-1-yl) ethan-1-one
Figure BDA0002321528230002972
Preparation of 1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (piperazin-1-yl) ethan-1-one reference example 247.
MS m/z(ESI):496.2[M+H] + .
Example 260
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230002981
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and pyridine-2-carboxylic acid (28mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (27.3mg, 21%).
1 H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.86(s，1H)，8.59(d，J＝4.4Hz，1H)，7.94(td，J＝7.7，1.6Hz，1H)，7.73-7.44(m，3H)，7.05-6.50(m，3H)，4.84(d，J＝28.0Hz，2H)，3.94(s，1H)，2.21(s，3H)，2.18-1.59(m，10H).
MS m/z(ESI):475.1[M+H] + .
Example 261
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-3-yl) methanone
Figure BDA0002321528230002982
Figure BDA0002321528230002991
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and pyridine-3-carboxylic acid (28mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (28.6 mg, 22%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.07(s，1H)，9.87(s，1H)，8.71-8.58(m，2H)，7.84(d，J＝7.6Hz，1H)，7.69(d，J＝6.0Hz，1H)，7.51(dd，J＝7.6，4.8Hz，1H)，6.96(d，J＝5.2Hz，1H)，6.68-6.50(m，2H)，4.83(d，J＝39.2Hz，2H)，3.78(s，1H)，2.21(s，3H)，2.13-1.61(m，10H).
MS m/z(ESI):475.1[M+H] + .
Example 262
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-4-yl) methanone
Figure BDA0002321528230002992
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and pyridine-4-carboxylic acid (28mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (34.5mg, 27%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.07(s，1H)，9.87(s，1H)，8.69(d，J＝6.0Hz，2H)，7.69(d，J＝5.6Hz，1H)，7.39(d，J＝5.6Hz，2H)，6.97(d，J＝6.0Hz，1H)，6.57(d，J＝7.6Hz，2H)，4.82(d，J＝41.6Hz，2H)，3.68(s，1H)，2.21(s，3H)，2.14-1.59(m，10H).
MS m/z(ESI):475.1[M+H] + .
Example 263
(1-methyl-1H-imidazol-2-yl) ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) methanone
Figure BDA0002321528230003001
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, and 1-methyl-1 h-imidazole-2-carboxylic acid (29mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a white solid (15.0 mg, 12%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.08(s，1H)，9.87(s，1H)，7.68(s，1H)，7.29(s，1H)，6.97(s，2H)，6.65(s，2H)，4.91-4.80(m，3H)，3.77(s，3H)，2.22(s，3H)，2.14-1.60(m，10H).
MS m/z(ESI):478.2[M+H] + .
Example 264
(1-methyl-1-hydro-imidazol-4-yl) ((3-exo) -3- ((4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) methanone
Figure BDA0002321528230003011
Preparation of (1-methyl-1 h-imidazol-4-yl) ((3-exo) -3- ((4- ((5-methyl-1 h-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) methanone reference example 250.
1 H NMR(400MHz，DMSO-d 6 )δ＝12.08(s，1H)，9.86(s，1H)，7.70-7.60(m，3H)，6.95(s，1H)，6.65(s，1H)，5.57(s，1H)，4.82(d，J＝65.2Hz，3H)，3.68(s，3H)，2.22(s，3H)，2.13-1.58(s，10H).
MS m/z(ESI):478.1[M+H] + .
Example 265
N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - ((3-exo) -8 (pyridin-3 ylsulfonyl) -8-azabicyclo [3.2.1]Octane-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0002321528230003012
Figure BDA0002321528230003021
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, N-dimethylformamide (5 mL) was added to dissolve it, DIPEA (46mg, 0.36mmol) was slowly added dropwise, stirring was carried out for 10 minutes in an ice-water bath, and pyridine-3-sulfonyl chloride (18mg, 0.1mmol) was added followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (5.6 mg, 13%).
1 H NMR(400MHz，DMSO)δ＝12.01(s，1H)，9.86(s，1H)，9.05(s，1H)，8.87(d，J＝4.4Hz，1H)，8.31(d，J＝8.0Hz，1H)，7.65(dd，J＝7.8Hz，5.0，2H)，6.97(s，1H)，6.78(s，1H)，6.54(s，1H)，4.33(s，2H)，3.17(d，J＝5.2Hz，1H)，2.14(s，3H)，1.99(s，2H)，1.76-1.56(m，4H)，1.35-1.26(m，2H).
MS m/z(ESI):497.1[M+H] + .
Example 266
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-2-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0002321528230003022
Preparation of N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-2-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 252.
1 H NMR(400MHz,CD 3 OD:CDCl 3 ,v/v＝1:2)δ8.70(d,J＝4.6Hz,1H),8.00(dt,J＝8.0,4.6Hz,2H),7.60(ddd,J＝6.8,4.8,1.8Hz,1H),7.35(d,J＝6.0Hz,1H),6.92(d,J＝6.0Hz,1H),6.19(s,1H),4.43(s,2H),4.40-4.32(m,1H),2.27(s,3H),2.15(ddd,J＝12.7,5.3,2.6Hz,2H),1.88-1.81(m,2H),1.80-1.70(m,2H),1.62(dd,J＝8.6,4.7Hz,2H).
MS m/z(ESI):497.1[M+H] + .
Example 267
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-2-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0002321528230003031
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.213mmol) was dispersed in 4M HCl 1, 4-epoxyhexacyclic (15 mL), the reaction was stirred at room temperature for 60 minutes, the solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10 mL), cooled to 0 deg.C, DIPEA (1.05mL, 6.39mmol) and pyridine-2-sulfonyl chloride (40mg, 0.224mmol) were added in this order, and the reaction mixture was stirred at 0 deg.C for 2.5 hours. The solvent was removed by concentration under reduced pressure and the residue was isolated by prep-HPLC to give the title compound as a white solid (12.4 mg, 25%).
1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),9.85(s,1H),8.78(d,J＝4.0Hz,1H),8.08(td,J＝7.7,1.4Hz,1H),7.96(d,J＝7.8Hz,1H),7.67(dd,J＝6.7,4.7Hz,2H),6.95(s,1H),6.59(d,J＝30.3Hz,2H),4.85-4.71(m,1H),4.18(s,2H),2.17(s,3H),2.05(dd,J＝12.8,4.9Hz,3H),1.68(d,J＝2.6Hz,7H).
MS m/z(ESI):511.1[M+H] + .
Example 268
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-3-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0002321528230003032
Preparation of N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-3-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 267.
1 H NMR(400MHz,CD 3 OD:CDCl 3 ,v/v＝1:1)δ9.11(s,1H),8.84(d,J＝3.9Hz,1H),8.29(d,J＝8.2Hz,1H),7.70-7.62(m,1H),7.39(d,J＝5.9Hz,1H),6.96(d,J＝5.8Hz,1H),6.62(s,1H),5.05-4.90(m,1H),4.34(d,J＝2.8Hz,2H),2.55-2.19(m,5H),2.19-1.61(m,8H).
MS m/z(ESI):511.1[M+H] + .
Example 269
N2- ((3-exo) -9- ((1-methyl-1H-imidazol-2-yl) sulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0002321528230003041
Preparation of N2- ((3-exo) -9- ((1-methyl-1H-imidazol-2-yl) sulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 267.
1 H NMR(400MHz，DMSO-d 6 )δ12.05(s，1H)，9.86(s，1H)，7.67(d，J＝2.9Hz，1H)，7.45(s，1H)，7.08(s，1H)，6.96(d，J＝4.9Hz，1H)，6.73-6.47(m，2H)，4.88-4.74(m，1H)，4.12(s，2H)，3.87(s，3H)，2.19(s，3H)，2.09(ddd，J＝5.5，5.1，1.0Hz，3H)，1.91-1.58(m，7H).
MS m/z(ESI):514.1[M+H] + .
Example 270
N, N-dimethyl-2- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) acetamide
Figure BDA0002321528230003042
Figure BDA0002321528230003051
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; n, N-dimethylformamide (5 mL) was then added to dissolve it, DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after the addition of 2-bromo-N, N-dimethylacetamide (38mg, 0.23mmol). The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (16.6 mg, 17%).
1 H NMR(400MHz，DMSO)δ＝12.00(s，1H)，9.80(s，1H)，7.63(s，1H)，6.74(d，J＝128.0Hz，3H)，4.62(s，1H)，3.42(s，2H)，3.04(s，3H)，2.86(s，2H)，2.77(s，3H)，2.16(s，3H)，1.96-1.47(m，10H).
MS m/z(ESI):455.2[M+H] + .
Example 271
N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - ((3-exo) -9- (pyridin-2-ylmethyl) -9-azabicyclo [3.3.1]Nonan-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0002321528230003052
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, this was dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes in an ice-water bath, and after adding 2- (chloromethyl) pyridine hydrochloride (38mg, 0.23mmol), the mixture was heated to 70 ℃ and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a white solid (20.8mg, 22%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.06(s，1H)，9.85(s，1H)，8.47(d，J＝4.0Hz，1H)，7.81-7.48(m，3H)，7.33-6.52(m，4H)，4.74(s，1H)，3.92(s，2H)，2.89(s，2H)，2.23(d，J＝13.6Hz，3H)，2.08-1.50(m，10H).
MS m/z(ESI):461.1[M+H] + .
Example 272
N 2 - ((3-exo) -9- ((1-methyl-1-hydro-imidazol-2-yl) methyl) -9-azabicyclo [3.3.1]Nonan-3-yl) -N 4 - (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0002321528230003061
N 2 - ((3-exo) -9- ((1-methyl-1-hydro-imidazol-2-yl) methyl) -9-azabicyclo [3.3.1]Nonan-3-yl) -N 4 - (5-methyl-1 hydro-pyrazol-3-yl) thieno [2,3-d]Preparation of pyrimidine-2, 4-diamine reference example 271.
1 H NMR(400MHz，DMSO-d 6 )δ＝12.06(s，1H)，9.84(s，1H)，7.67(s，1H)，7.08(s，1H)，6.95(s，1H)，6.74-6.55(m，3H)，4.69(s，1H)，3.91(s，2H)，3.69(s，3H)，2.84(s，2H)，2.20(s，3H)，2.01-1.66(m，10H).
MS m/z(ESI):464.2[M+H] + .
Example 273
3- ((3-exo)) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003071
The first step is as follows: preparation of (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0002321528230003072
2, 4-dichlorothieno [2,3-d ] pyrimidine (100mg, 0.49mmol), (3-amino-1H-pyrazol-5-yl) methanol (55mg, 0.49mmol), DIPEA (190mg, 1.47mmol) were added to N' N-dimethylformamide (2 mL), and the reaction mixture was stirred at 70 ℃ overnight. Concentrated under reduced pressure and the crude product was isolated and purified by flash column chromatography on silica gel to give the title compound as a yellow solid (100mg, 73%).
MS m/z(ESI):282.0[M+H] + .
The second step is that: preparation of tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230003073
(3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg, 0.36mmol), N-Boc-exo-3-aminotropane acetate (113mg, 0.40mmol), DIPEA (140mg, 1.08mmol) were added to N-butanol (2.5 mL), the reaction liquids were uniformly mixed, reacted under microwave heating at 150 ℃ for 10 hours, cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash chromatography to give the title compound as a pale yellow silica gel column solid (60mg, 35%).
MS m/z(ESI):472.0[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003081
Tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (60mg, 0.13mmol) was dissolved in methanol (10 mL), followed by slow addition of dioxane hydrochloride (4N, 2.5 mL) to the reaction mixture at room temperature for 2 hours, concentration under reduced pressure, addition of the resulting crude product to a solution of a mixture of methanol (15 mL), DIPEA (0.5 mL) and acrylonitrile (1 mL), dropwise addition at room temperature for 2 hours, concentration under reduced pressure, and separation and purification by prep-HPLC to give the title compound as a white solid (11.6mg, 21%).
1 H NMR(400MHz，CD 3 OD)δ7.39(dd，J＝6.0Hz，1H)，6.99(dd，J＝5.6Hz，1H),6.02-6.04(m,1H)，4.60(s,2H)，4.21-4.24(m，1H),3.45-3.42(m,2H)，2.83(s，2H)，2.69-2.65(m，2H),2.08-1.91(m，6H)，1.69(t，J＝12.4Hz，2H).
MS m/z(ESI):425.1[M+H] + .
Example 274
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003082
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 273.
MS m/z(ESI):439.2[M+H] + .
Example 275
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003091
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 273.
MS m/z(ESI):453.2[M+H] + .
Example 276
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003092
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 273.
MS m/z(ESI):530.2[M+H] + .
Example 277
3- ((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003093
The first step is as follows: preparation of tert-butyl- (3-exo) -3- ((6-methyl-4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230003101
To a solution of 2-chloro-6-methyl-N- (5-methyl-1 hydro-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (200mg, 0.72mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (194mg, 0.86mmol), DIPEA (186mg, 1.44mmol) in this order, followed by stirring under microwave conditions at 160 ℃ for 15 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale yellow solid (124mg, 37%).
MS m/z(ESI):470.2[M+H] + .
The second step: preparation of 3- ((3-exo) -3- ((6-methyl-4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003102
Dissolving tert-butyl- (3-exo) -3- ((6-methyl-4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (124mg, 0.26mmol) in 1, 4-epoxyhexacyclic solution (4.0N, 5 mL), stirring at room temperature for 30 minutes, and then concentrating the reaction solution; then, methanol (10 mL) was added to dissolve it, DIPEA (137mg, 1.06mmol) was added slowly dropwise, and the mixture was stirred at room temperature for 10 minutes, followed by addition of acrylonitrile (21mg, 0.39mmol) and further stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (12.7mg, 12%).
1 H NMR(400MHz,DMSO)δ＝9.70(s,1H),7.30(s,1H),6.59(s,3H),4.15(s,1H),3.29(s,2H),2.61(s,4H),2.39(s,3H),2.22(s,3H),1.90(s,2H),1.78-1.50(m,6H).
MS m/z(ESI):423.2[M+H] + .
Example 278
3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003111
The first step is as follows: preparation of 5-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine
Figure BDA0002321528230003112
To a solution of 5, 7-dichlorothiazolo [5,4-d ] pyrimidine (206mg, 1mmol) in dimethylsulfoxide (10 mL) was added 3-amino-5-methylpyrazole (116mg, 1.2 mmol), DIPEA (258mg, 2mmol) in this order, followed by heating and stirring at 70 ℃ for one hour. After completion of the reaction, water (50 mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (200mg, 75%).
MS m/z(ESI):267.0[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230003113
To a solution of 5-chloro-N- (5-methyl-1H-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine (200mg, 0.75mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (216mg, 0.9mmol), DIPEA (193mg, 1.5mmol) in this order, followed by stirring under microwave conditions at 160 ℃ for 15 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a pale yellow solid (232mg, 66%).
MS m/z(ESI):471.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003121
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (232mg, 0.49mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated; then, methanol (10 mL) was added to dissolve it, DIPEA (127mg, 0.98mmol) was added slowly dropwise, and stirring was continued at room temperature for 10 minutes, followed by addition of acrylonitrile (39mg, 0.74mmol) and stirring continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to give the title compound as a pale yellow solid (63mg, 30%).
1 H NMR(400MHz，DMSO)δ＝12.06(s，1H)，9.29(s，1H)，8.76(d，J＝18.8Hz，1H)，6.92(d，J＝7.2Hz，1H)，6.57(s，1H)，4.67(s，1H)，3.31(s，2H)，2.58(t，J＝6.2Hz，4H)，2.19(s，3H)，2.00-1.65(m，10H).
MS m/z(ESI):424.2[M+H] + .
Example 279
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003122
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230003131
NaH (120mg, 3.01mmol, 60%) was added portionwise to a solution of tert-butyl (3-exo) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (427mg, 1.88mmol) in N, N-dimethylformamide (2 mL) at room temperature, stirred for 5 minutes at room temperature, then a solution of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376 mmol) in N, N-dimethylformamide (1 mL) was added dropwise and the mixture was heated to 120 ℃ under nitrogen and stirred for 2 hours. The reaction solution was cooled to room temperature, and then poured into ice water (10 mL) and stirred for 10 minutes, followed by filtration, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with a saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the organic solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound as a yellow oil (149mg, 87%).
The second step is that: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003132
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octane-8-carboxylate (77mg, 0.1699 mmol) was dissolved in methanol (2 mL), 4M HCl in 1, 4-dioxane (2 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1 mL), DIPEA (109mg, 0.844mmol) and acrylonitrile (45mg, 0.844mmol) were successively added, and the resulting reaction mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was preliminarily separated and purified by silica gel chromatography and further separated and purified by preparative TLC to give the title compound as a gray solid (7 mg, 10%).
1 H NMR(400MHz，CD 3 OD)δ7.50(d，J＝6.1Hz，1H)，7.22(d，J＝5.9Hz，1H)，6.51(s，1H)，5.43-5.26(m，1H)，3.44-3.37(m，2H)，2.78(t，J＝6.9Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.33(s，3H)，2.12-2.00(m，4H)，1.86-1.74(m，4H).
MS m/z(ESI):410.1[M+H] + .
Example 280
3- ((3-exo) -3- ((6- (methoxymethyl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003141
Preparation of 3- ((3-exo) -3- ((6- (methoxymethyl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 277.
MS m/z(ESI):453.2[M+H] + .
Example 281
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6-morpholinothieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003142
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6-morpholinothieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 277.
MS m/z(ESI):494.2[M+H] + .
Example 282
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (morpholinomethyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003151
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (morpholinomethyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 277.
MS m/z(ESI):508.3[M+H] + .
Example 283
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- ((4-methylpiperazin-1-yl) methyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003152
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- ((4-methylpiperazin-1-yl) methyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 277.
MS m/z(ESI):535.3[M+H] + .
Example 284
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (pyridin-3-ylthio) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003161
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (pyridin-3-ylthio) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 277.
MS m/z(ESI):532.2[M+H] + .
Example 285
3- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003162
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.22mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10 mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was continued at room temperature for 10 minutes, and after the addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (23.2mg, 21%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.07(s，1H)，9.74(s，1H)，7.90(s，1H)，7.00(s，1H)，6.54(s，2H)，4.27(s，1H)，4.13(s，2H)，4.04(t，J＝8.4Hz，2H)，3.98-3.89(m，2H)，3.80(dd，J＝15.2，6.0Hz，1H)，2.23(s，3H)，1.99(s，4H)，1.84(d，J＝7.2Hz，2H)，1.63(s，2H).
MS m/z(ESI):500.1[M+H] + .
Example 286
1- (((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003171
Preparation of 1- (((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile is according to example 267.
1 H NMR(400MHz，DMSO-d 6 )δ12.02(s，1H)，9.64(s，1H)，6.77-6.45(m，3H)，4.25-4.23(m，1H)，4.12(s，2H)，4.06-4.02(m，2H)，3.95-3.88(m，2H)，3.83-3.77(m，1H)，2.24-2.21(m，4H)，1.99-1.98(m，5H)，1.84-1.81(m，2H)，1.64-1.59(m，3H).
MS m/z(ESI):513.1[M+H] + .
Example 287
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230003172
Preparation of 2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one is according to example 285.
1 H NMR(400MHz，DMSO-d 6 )δ＝12.06(s，1H)，9.72(s，1H)，7.89(s，1H)，6.99(s，1H)，6.49(d，J＝58.8Hz，2H)，4.59-4.28(m，3H)，3.04(s，2H)，2.15(s，9H)，1.98-1.80(m，6H)，1.59-1.45(m，2H).
MS m/z(ESI):441.1[M+H] + .
Example 288
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-morpholinoethane-1-one
Figure BDA0002321528230003181
The first step is as follows: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230003182
To a solution of 2-chloro-N- (5-methyl-1 h-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (250mg, 0.94mmol) in N-butanol (10 mL) were added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (271mg, 1.13mmol), DIPEA (242mg, 1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a pale white solid (150mg, 34%).
MS m/z(ESI):470.1[M+H] + .
The second step is that: preparation of tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230003183
Tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then, 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5 mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, and stirred for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (33mg, 0.23mmol) was added and then stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (17.8mg, 17%).
1 H NMR(400MHz，DMSO-d 6 )δ＝11.99(s，1H)，9.69(s，1H)，7.84(s，1H)，7.07-6.23(m，3H)，4.77(s，1H)，4.58(s，1H)，4.30(s，1H)，3.52(d，J＝4.0Hz，4H)，3.10-3.01(m，2H)，2.32(s，3H)，2.14(s，2H)，2.09-1.39(m，10H).
MS m/z(ESI):497.1[M+H] + .
Example 289
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) ethane-1-one
Figure BDA0002321528230003191
Preparation of 1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) ethan-1-one reference example 247.
MS m/z(ESI):441.2[M+H] + .
Example 290
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230003192
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone reference example 288.
MS m/z(ESI):475.2[M+H] + .
Example 291
(1-methyl-1H-imidazol-2-yl) ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) methanone
Figure BDA0002321528230003201
Preparation of (1-methyl-1H-imidazol-2-yl) ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) methanone reference example 288.
MS m/z(ESI):478.2[M+H] + .
Example 292
2- (dimethylamino) -1- ((1R, 3r, 5S) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0002321528230003202
Preparation of 2- (dimethylamino) -1- ((1r, 3r, 5s) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one is according to example 242.
MS m/z(ESI):441.2[M+H] + .
Example 293
N, N-dimethyl-2- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) acetamide
Figure BDA0002321528230003211
Dissolving tert-butyl- (3-exo) -3- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.21mmol) in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirring at room temperature for 30 minutes, and then concentrating the reaction solution; n, N-dimethylformamide (5 mL) was then added to dissolve it, DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after the addition of 2-bromo-N, N-dimethylacetamide (38mg, 0.23mmol). The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (16.4 mg, 17%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.05(s，1H)，9.74(s，1H)，7.90(d，J＝4.0Hz，1H)，7.14-6.30(m，3H)，4.15(s，1H)，3.32-3.23(m，4H)，3.08(s，3H)，2.83(s，3H)，2.22(s，3H)，1.97(s，2H)，1.82-1.55(m，6H).
MS m/z(ESI):441.1[M+H] + .
Example 294
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -6-methylthiothieno [3, 2-d-pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003212
The first step is as follows: preparation of (3- ((2-chloro-6-methylthiophen [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0002321528230003221
2, 4-dichloro-6-methylthioeno [3,2-d ] pyrimidine (200mg, 0.91mmol), (3-amino-1H-pyrazol-5-yl) methanol (120mg, 1.09mmol), DIPEA (350mg, 2.73mmol) were dissolved in N, N-dimethylformamide (10 mL), mixed well, and reacted at 70 ℃ overnight. After cooling to room temperature, the reaction mixture was extracted with water (30 mL) and ethyl acetate (20mL. Multidot.3), the organic phases were combined, concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a white solid (200mg, 75%).
MS m/z(ESI):296.0[M+H] + .
The second step: preparation of tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -6-methylthieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0002321528230003222
(3- ((2-chloro-6-methylthiophene [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (150mg, 0.51mmol), tert-butyl (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate oxalate (200mg, 0.61mmol) and DIPEA (200mg, 1.53mmol) were added to n-butanol (3 mL), and after uniform mixing, the reaction mixture was heated by microwave at 165 ℃ for 8 hours, cooled to room temperature, and the reaction solution was concentrated under reduced pressure, and the obtained crude product (200 mg) was used in the next reaction without purification.
MS m/z(ESI):500.1[M+H] + .
The third step: preparation of (3- ((2- (((3-exo) -9-azabicyclo [3.3.1] nonan-3-yl) amino) -6-methylthio [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0002321528230003231
To a solution of tert-butyl (3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -6-methylthioeno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (200mg, 0.40mmol) in methanol (10 mL) was slowly added dropwise dioxane hydrochloride (4n, 5 mL), the reaction solution was allowed to react at room temperature for 3 hours, concentrated under reduced pressure, and the resulting crude product was isolated and purified by prep-HPLC to give the title compound as a yellow solid (100mg, 63%).
MS m/z(ESI):400.1[M+H] + .
The fourth step: preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) -6-methylthieno [3, 2-d-pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0002321528230003232
(3- ((2- (((3-exo) -9-azabicyclo [3.3.1] nonan-3-yl) amino) -6-methylthiophene [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg, 0.25mmol), acrylonitrile (0.2 mL), and DIPEA (0.1 mL) were added to methanol (10 mL), and after uniform mixing, the mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the resulting crude product was isolated and purified by prep-HPLC to give the title compound as a white solid (11.7 mg, 10%).
1 H NMR(400MHz，DMSO-d 6 )δ12.28(s，1H)，10.12(s，1H)，7.09-6.64(m，2H)，6.29-6.23(s，1H)，5.22-4.94(m，1H)，4.67-4.37(m，3H)，2.95(s，2H)，2.85-2.81(m，2H)，2.70-2.57(m，5H)，1.95-1.49(m，10H).
MS m/z(ESI):453.2[M+H] + .
Example 295
3- ((3-exo) -3- ((1-methyl-4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) -1-hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003241
The first step is as follows: preparation of 6-chloro-1-methyl-N- (5-methyl-1-hydro-pyrazol-3-yl) -1-hydro-pyrazolo [3,4-d ] pyrimidin-4-amine
Figure BDA0002321528230003242
To a solution of 4, 6-dichloro-1-methyl-1-hydro-pyrazolo [3,4-d ] pyrimidine (203mg, 1mmol) in ethanol (10 mL) was added 3-amino-5-methylpyrazole (117mg, 1.2 mmol), DIPEA (258mg, 2mmol) in this order, and the mixture was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 98) to obtain the title compound as a yellow solid (250mg, 95%).
MS m/z(ESI):264.0[M+H] + .
The second step: preparation of tert-butyl- (3-exo) -3- ((1-methyl-4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -1 hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0002321528230003243
To a solution of 6-chloro-1-methyl-N- (5-methyl-1-hydro-pyrazol-3-yl) -1-hydro-pyrazolo [3,4-d ] pyrimidin-4-amine (132mg, 0.5 mmol) in N-butanol (5 mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (170mg, 0.75mmol), DIPEA (129mg, 1mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a white solid (165mg, 73%).
MS m/z(ESI):454.2[M+H] + .
The third step: preparation of 3- ((3-exo) -3- ((1-methyl-4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) -1-hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0002321528230003251
Tert-butyl- (3-exo) -3- ((1-methyl-4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) -1 hydro-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (165mg, 0.36mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 5mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; methanol (10 mL) was then added to dissolve it, DIPEA (186mg, 1.44mmol) was added slowly dropwise, stirring at room temperature for 10 minutes, acrylonitrile (29mg, 0.55mmol) was added and stirring continued for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and subjected to prep-HPLC to obtain the title compound as a white solid (60.4 mg, 41%).
1 H NMR(400MHz，DMSO-d 6 )δ＝11.96(s，1H)，10.04(s，1H)，7.99(s，1H)，6.64(s，2H)，4.18(s，1H)，3.63(d，J＝20.4Hz，3H)，3.22(s，2H)，2.55(s，4H)，2.17(s，3H)，1.84(s，2H)，1.73-1.48(m，6H).
MS m/z(ESI):407.2[M+H] + .
Example 296
1- ((3-exo) -3- ((1-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-morpholinoethane-1-one
Figure BDA0002321528230003252
Preparation of 1- ((3-exo) -3- ((1-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-morpholinoethan-1-one refers to example 246.
MS m/z(ESI):495.2[M+H] + .
Example 297
((3-exo) -3- ((1-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230003261
Preparation of ((3-exo) -3- ((1-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone reference example 260.
MS m/z(ESI):473.2[M+H] + .
Example 298
3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0002321528230003262
The first step is as follows: preparation of tert-butyl cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate
Figure BDA0002321528230003263
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376 mmol), tert-butyl cis-5-aminohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (102mg, 0.452mmol) and DIPEA (146mg, 1.13mmol) were added to NMP (1 mL), and the mixture was heated to 160 ℃ by microwave heating under nitrogen protection for 8 hours. The reaction was cooled to room temperature and poured into ice water (10 mL) with stirring for 10 min, filtered, the filter cake was washed with water (15 mL) and dried in vacuo to give the title compound as a yellow solid (171 mg, crude).
The second step is that: preparation of 3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0002321528230003271
Tert-butylcis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (86mg, 0.188mmol) was dissolved in methanol (2 mL), 4M HCl 1, 4-dioxane (2 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2 mL), DIPEA (1218mg, 0.93mmol) and acrylonitrile (15mg, 0.282mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 16 hours. The reaction was diluted with DCM (20 mL), washed with water (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was isolated and purified by silica gel chromatography to give the title compound as a white solid (17mg, 22%).
1 H NMR(400MHz，CD 3 OD)δ7.36(d，J＝6.0Hz，1H)，7.02-6.86(m，1H)，6.54(s，0.6H)，5.80(s，0.4H)，4.34-4.09(m，1H)，2.86-2.72(m，4H)，2.73-2.57(m，4H)，2.40-2.19(m，7H)，1.57-1.37(m，2H).
MS m/z(ESI):409.1[M+H] + .
Example 299
3- (cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1 hydro) -yl) propionitrile
Figure BDA0002321528230003272
The first step is as follows: preparation of tert-butyl-cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1 hydro) -carboxylate
Figure BDA0002321528230003281
To a solution of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (100mg, 0.38mmol) in N-butanol (5 mL) was added tert-butyl-cis-5-aminohexahydrocyclopenta [ c ] pyrrole-2 (1-hydro) -carboxylate (102mg, 0.45mmol), DIPEA (98mg, 0.76mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 95) to obtain the title compound as a pale yellow solid (80mg, 46%).
MS m/z(ESI):456.2[M+H] + .
The second step is that: preparation of 3- (cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1 hydro) -yl) propionitrile
Figure BDA0002321528230003282
Tert-butyl-cis-5- ((4- ((5-methyl-1-hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1-hydro) -carboxylate (80mg, 0.18mmol) was dissolved in 1, 4-epoxyhexacyclic hydrochloride solution (4.0N, 2mL), and after stirring at room temperature for 30 minutes, the reaction solution was concentrated; methanol (5 mL) was then added to dissolve it, DIPEA (93mg, 0.72mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (14mg, 0.27mmol) was added followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained product was subjected to prep-HPLC to obtain the title compound as a white solid (26.3mg, 37%).
1 H NMR(400MHz，DMSO-d 6 )δ＝12.30(s，1H)，9.92(s，1H)，7.90(s，1H)，7.51-6.25(m，3H)，4.11(s，1H)，2.66(dd，J＝13.6，7.2Hz，6H)，2.22(s，8H)，1.31(s，3H).
MS m/z(ESI):409.1[M+H] + .
Example 300
3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-
2 (1H) -yl) propionitrile
Figure BDA0002321528230003291
Preparation of 3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile reference example 281.
1 H NMR(400MHz，DMSO-d 6 )δ12.14(s，1H)，10.16(s，1H)，8.29(s，1H)，7.54(t，J＝7.5Hz，1H)，7.32(d，J＝8.2Hz，2H)，7.09(t，J＝7.2Hz，1H)，6.63(s，1H)，4.26-4.09(m，1H)，2.63(dd，J＝25.8，13.5Hz，8H)，2.42-1.98(m，7H)，1.34(dd，J＝15.0，9.5Hz，2H).
MS m/z(ESI):403.2[M+H] + .
Example 301
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0002321528230003292
The first step is as follows: preparation of tert-butyl 4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidine-1-carboxylate
Figure BDA0002321528230003293
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376 mmol), 1-BOC-4-aminopiperidine (108mg, 0.539mmol) and DIPEA (146mg, 1.13mmol) were added to NMP (1 mL), and the mixture was heated to 130 ℃ by microwave heating under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and then poured into ice water (10 mL) and stirred for 10 min, filtered, the filter cake was washed with water (5 mL) and dried in vacuo to give the title compound as a yellow solid (100 mg, crude).
The second step: preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0002321528230003301
Tert-butyl 4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidine-1-carboxylate (100mg, 0.233mmol) was dissolved in methanol (2 mL), 4M HCl in ethyl acetate (2 mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2 mL), DIPEA (150mg, 1.17mmol) and acrylonitrile (62mg, 1.17mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 1 hour. The reaction was diluted with DCM (20 mL), washed with water (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was isolated and purified by silica gel chromatography to give the title compound as a white solid (18mg, 20%).
1 H NMR(400MHz，CD 3 OD)δ7.37(d，J＝6.0Hz，1H)，6.97(d，J＝6.1Hz，1H)，6.55(s，0.5H)，5.81(s，0.5H)，3.92-3.74(m，1H)，3.04-2.88(m，2H)，2.81-2.57(m，4H)，2.44-2.15(m，5H)，2.14-1.97(m，2H)，1.73-1.52(m，2H).
MS m/z(ESI):383.1[M+H] + .
Example 302
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003311
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 237.
1 H NMR(400MHz，CD 3 OD)δ7.38(d，J＝6.0Hz，1H)，6.99(d，J＝6.0Hz，1H)，6.49(s，0.5H)，5.83(s，0.5H)，4.20-4.10(m，2H)，4.07-3.99(m，2H)，3.99-3.89(m，1H)，3.77-3.61(m，3H)，3.09-2.99(m，2H)，2.28(s，3H)，2.17-2.06(m，2H)，1.67-1.51(m，2H).
MS m/z(ESI):474.0[M+H] + .
Example 303
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2- (methylamino) ethan-1-one
Figure BDA0002321528230003312
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2- (methylamino) ethan-1-one refers to example 247.
MS m/z(ESI):401.2[M+H] + .
Example 304
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one
Figure BDA0002321528230003321
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one refers to example 246.
MS m/z(ESI):457.2[M+H] + .
Example 305
(4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230003322
Preparation of (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone reference example 260.
MS m/z(ESI):435.2[M+H] + .
Example 306
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0002321528230003323
Preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile reference example 60.
MS m/z(ESI):383.2[M+H] + .
Example 307
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003331
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 60.
MS m/z(ESI):474.1[M+H] + .
Example 308
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one
Figure BDA0002321528230003332
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one refers to example 246.
MS m/z(ESI):457.2[M+H] + .
Example 309
(4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone
Figure BDA0002321528230003341
Preparation of (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone reference example 260.
MS m/z(ESI):435.2[M+H] + .
Example 310
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0002321528230003342
Preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) propionitrile reference example 301.
1 H NMR(400MHz，CD 3 OD:CDCl 3 ，v/v＝1:1)δ8.03(d，J＝8.1Hz，1H)，7.59(d，J＝7.9Hz，1H)，7.44(s，1H)，7.20(t，J＝7.4Hz，1H)，6.63(s，1H)，5.92(s，1H)，4.01-3.87(m，1H)，2.98(d，J＝11.6Hz，2H)，2.77(t，J＝6.9Hz，2H)，2.64(t，J＝6.9Hz，2H)，2.45-2.22(m，5H)，2.19-2.07(m，2H)，1.65(td，J＝14.0，3.4Hz，2H).
MS m/z(ESI):377.1[M+H] + .
Example 311
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003351
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 213.
1 H NMR(400MHz，CD 3 OD:CDCl 3 ，v/v＝1:1)δ8.04(d，J＝8.1Hz，1H)，7.65-7.59(m，1H)，7.45(d，J＝8.2Hz，1H)，7.22(t，J＝7.5Hz，1H)，6.31(s，1H)，4.17(t，J＝8.3Hz，2H)，4.12-4.01(m，3H)，3.74(d，J＝12.7Hz，2H)，3.61(ddd，J＝15.1，8.7，6.4Hz，1H)，3.06(t，J＝11.3Hz，2H)，2.32(s，3H)，2.21-2.11(m，2H)，1.64(td，J＝13.6，3.3Hz，2H).
MS m/z(ESI):468.1[M+H] + .
Example 312
3- (4- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0002321528230003352
Preparation of 3- (4- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) piperidin-1-yl) propionitrile reference example 111.
MS m/z(ESI):377.2[M+H] + .
Example 313
1- ((4- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0002321528230003361
Preparation of 1- ((4- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile is referred to example 111.
MS m/z(ESI):468.2[M+H] + .
Example 314
3- (6- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptan-2-yl) propionitrile
Figure BDA0002321528230003362
The first step is as follows: preparation of tert-butyl 6- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate
Figure BDA0002321528230003363
5, 7-dichloro-1, 6-naphthyridine (200mg, 1.00mmol), tert-butyl 6-amino-2-azaspiro [3.3] heptane-2-carboxylate (256 mg, 1.21mmol), DIPEA (324mg, 2.51mmol) were added to NMP (2 mL) respectively, and stirred at 120 ℃ for 3 hours. The reaction solution was cooled to room temperature, poured into ice water (20 mL), stirred for 10 minutes, extracted with ethyl acetate, and the organic phases were combined, washed with a saturated aqueous solution of sodium chloride, collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography to give the title compound as a brown oil (340mg, 91%).
The second step is that: preparation of tert-butyl 6- ((7- ((1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate
Figure BDA0002321528230003371
Tert-butyl 6- ((7-chloro-1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (100mg, 0.267mmol), 1-BOC-3-amino-5-methylpyrazole (79mg, 0.400mmol), cesium carbonate (174mg, 0.534mmol), XPhos Pd G2 (105mg, 0.134mmol), XPhos (127mg, 0.267mmol) were added to dioxane (5 mL), respectively, and after nitrogen substitution three times, the reaction was stirred at 100 ℃ for 4 hours. The reaction solution was diluted with ethyl acetate (20 mL), filtered through celite, the filtrate was washed with water and saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography to give the title compound as a yellow oil (44 mg, crude product).
The third step: preparation of 3- (6- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptan-2-yl) propionitrile
Figure BDA0002321528230003372
Tert-butyl 6- ((7- ((1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (66 mg, crude) was dissolved in methanol (2 mL), 4M HCl 1, 4-dioxane (2 mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1 mL), DIPEA (48mg, 0.370mmol) and acrylonitrile (10mg, 0.185mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the residue was preliminarily separated and purified by silica gel chromatography and further separated and purified by prep-HPLC to give the title compound as a yellow solid (6 mg, 12%).
1 H NMR(400MHz，CD 3 OD)δ8.55(s，1H)，8.38(d，J＝8.2Hz，1H)，7.16-6.98(m，1H)，6.64(s，0.4H)，6.11(s，0.6H)，4.61-4.37(m，1H)，3.56-3.46(m，2H)，3.37-3.32(m，2H)，2.83-2.63(m，4H)，2.55-2.44(m，2H)，2.39-2.16(m，5H).
MS m/z(ESI):389.2[M+H] + .
Example 315
N5- ((3-exo) -8- ((1H-pyrazol-4-yl) sulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -N7- (5-methyl-1H-pyrazol-3-yl) -1, 6-naphthyridine-5, 7-diamine
Figure BDA0002321528230003381
Preparation of N5- ((3-exo) -8- ((1H-pyrazol-4-yl) sulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -N7- (5-methyl-1H-pyrazol-3-yl) -1, 6-naphthyridine-5, 7-diamine reference example 111.
1 H NMR(400MHz,DMSO-d 6 )δ＝9.03(s,1H),8.78(s,1H),8.59(d,J＝2.8Hz,1H),8.49(s,2H),8.37(d,J＝8.4Hz,1H),8.32(s,1H),7.21(d,J＝8.0Hz,1H),6.98(dd,J＝8.4,4.0Hz,1H),6.69(s,1H),6.05(s,1H),4.62(s,1H),4.35(s,2H),2.16(s,3H),2.10-2.02(m,2H),1.78-1.73(m,4H),1.41-1.32(m,2H).
MS m/z(ESI):480.2[M+H] + .
Example 316
3- (endo-6- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0002321528230003382
Preparation of 3- (endo-6- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) -1, 6-naphthyridin-5-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 111.
MS m/z(ESI):375.2[M+H] + .
Example 317
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0002321528230003391
Preparation of 3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 62.
MS m/z(ESI):381.2[M+H] + .
Example 318
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0002321528230003392
Preparation of 3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 60.
MS m/z(ESI):381.2[M+H] + .
Example 319
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0002321528230003393
Preparation of 3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 4.
MS m/z(ESI):375.2[M+H] + .
Biological test evaluation
The present invention is further described and explained below in connection with test examples, which are not intended to limit the scope of the present invention.
Test example 1 measurement of inhibitory Effect of the Compound of the present invention on JAK kinase Activity
The purpose of the experiment is as follows: the purpose of this test example was to test the activity of compounds on inhibition of JAK kinase activity.
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the experiment adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition effect of the compound on the JAK kinase activity, and obtains the half inhibition concentration IC of the compound on the JAK kinase activity 50 。
The specific experimental operations were as follows:
the kinase reaction was performed in white 384-well plates (PerkinElmer) with 1-5. Mu.L of DMSO and ddH per well 2 O diluted compounds of different concentrations, 1-5. Mu.L of the corresponding vehicle was added to the positive control wells, followed by 1-5. Mu.L of kinase buffer (HEPES 50-250mM, mgCl. For each well) 2 5-20mM, etc.), 1-5. Mu.L of kinase buffer is added to the negative control wells, 1-5 ul of a substrate mixture containing a polypeptide substrate and ATP is added, incubation is performed at room temperature for 0.5-5 hours, 10ul of EDTA and a detection solution containing a labeled antibody are added, incubation is performed at room temperature for 1-24 hours, fluorescence signal values at about 620nM and 665nM are measured for each well by a BioTek Synergy H1 microplate reader, and the inhibition ratio is calculated from the fluorescence signal values. Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition =100- [ (test compound value-negative control value) for wells treated with compound was calculated by plating positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate]V (positive control value-negative control value) × 100}. IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
The experimental conclusion is that:
the above scheme shows that the compounds of the examples shown in the present invention show the biological activities in the JAK1/2/3/TYK2 kinase activity assay as shown in the following Table 1.
TABLE 1
Figure BDA0002321528230003401
Figure BDA0002321528230003411
Figure BDA0002321528230003421
Figure BDA0002321528230003431
Figure BDA0002321528230003441
Figure BDA0002321528230003451
Figure BDA0002321528230003461
From the above table, it can be seen that: the compounds of the above examples can obviously inhibit the enzymatic activity of JAK1/2/3/TYK2 kinase, and partial compounds show strong inhibition effect on JAK1/2/3/TYK2 kinase (NA indicates no detection).
Test example 2 measurement of inhibitory Effect of the Compound of the present invention on the JAK-STAT Signal pathway of cells
The purpose of the experiment is as follows:
the purpose of this test example was to test the activity of compounds on inhibition of the JAK-STAT signaling pathway in cells.
An experimental instrument:
microplate shaker (88880024) available from Thermo Scientific TM Company(s)
Centrifuge (5702R) from Eppendorf
Pipettes were purchased from Eppendorf Inc
The microplate reader is purchased from BioTek company, USA, and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps:
the experiment adopts a U266 cell line, activates a JAK-STAT signal channel through INF-alpha stimulation, detects the inhibition activity of a compound on the phosphorylation of downstream STAT3 of the compound, and obtains the half inhibition concentration IC of the compound on the activity of the JAK-STAT signal channel 50 。
The specific experimental operations were as follows:
3-12 mu L of U266 fine particles are paved in a 384-well detection plate, the number of cells in each well is 100-300K, 2 mu L of the compound solution diluted in a gradient way is added, and the mixture is incubated for 2 hours at room temperature and 350rpm with shaking. After 2 hours, 2. Mu.L of INF-. Alpha.was added to the solution at a final concentration of 1000U/mL, and the mixture was shaken at room temperature for 15 minutes. 2-5. Mu.L (5X) of LANCE Ultra Lysis Buffer 2 solution was added thereto, and the mixture was shaken at room temperature for 2 hours. After 2 hours, 5. Mu.L of a solution of LANCE Ultra Eu-labeled Anti-STAT3 Anti (PerkinElmer) at a final concentration of 0.5nM and a solution of LANCE Ultra high-labeled Anti-STAT3 Anti (PerkinElmer) at a final concentration of 5nM were added and incubated overnight at room temperature. Measuring 665nm fluorescence signal value of each plate hole by a microplate reader, calculating inhibition rate through the fluorescence signal value, and obtaining IC of the compound through curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition =100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data for wells treated with compound over positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate]/(positive control value-negative control value) × 100}. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
And (4) experimental conclusion:
the above scheme shows that the compound of the embodiment shown in the invention has the following biological activity on JAK-STAT signal pathway activity of U266 cells in the following table 2.
TABLE 2
Figure BDA0002321528230003471
Figure BDA0002321528230003481
From the above table, it can be seen that: the compound of the above example has obvious inhibition effect on the JAK-STAT signal pathway activity of human myeloma cell U266.
Test 3, balb/C mouse pharmacokinetic assay
1. The research aims are as follows:
Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of example 1, example 60, example 169, example 170, example 171, example 179, example 191, example 213, example 214, example 237, example 238, example 244, example 246, example 247, example 257, example 260, example 262, example 263, example 267, example 277, example 278, example 279, example 288, example 295, example 299 and example 301 in mice after oral administration at a dose of 5mg/kg (plasma and colon, ileum tissue), and to screen compounds with PK excellence for further studies by analyzing the drug concentrations in the colon and ileum, as well as the colon/ileum drug concentration and the colon/plasma drug concentration ratio.
2. Test protocol
2.1 test drugs:
embodiments 1, 60, 169, 170, 171, 179, 191, 213, 214, 237, 238, 244, 246, 247, 257, 260, 262, 263, 267, 277, 278, 279, 288, 295, 299 and 301 of the present invention are self-made.
2.2 test animals:
Balb/C Mouse group contains 12 animals per group, male, shanghai Jitsie laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.3 administration:
12 mice per group, male, balb/C; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10mL/kg.
2.4 sample collection:
mice were dosed with CO before and after dosing at 0, 0.5, 1, 2, 3, 5 and 7 hours 2 Sacrifice, blood sampling 0.2mL of the heart, placing in EDTA-K 2 Centrifuging at 4 deg.C and 6000rpm for 6 min in a test tube to separate plasma, and storing at-80 deg.C; the ileum is taken near the cecal end and is about 4-5cm long; the colon is also taken from the proximal cecum end, about 2-3cm in length, taken out, weighed, placed in a 2mL centrifuge tube, and stored at-80 ℃.
2.5 sample treatment:
1) Plasma samples 40uL were precipitated by addition of 160uL acetonitrile, mixed and centrifuged at 3500 Xg for 5-20 minutes.
2) Plasma and intestinal homogenate samples 30. Mu.L were precipitated by adding 90. Mu.L acetonitrile containing internal standard (100 ng/mL), mixed and centrifuged at 13000rpm for 8 minutes.
3) 70uL of the treated supernatant solution was added to 70uL of water, vortexed and mixed for 10 minutes, and then 20 uL of the supernatant solution was subjected to LC/MS/MS analysis for the concentration of the test compound, and the LC/MS/MS analyzer: AB Sciex API 4000Qtrap.
2.6 liquid phase analysis
● Liquid phase conditions: shimadzu LC-20AD pump
● A chromatographic column: agilent ZORBAX XDB-C18 (50X 2.1mm,3.5 μm) mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
● Flow rate: 0.4mL/min
● Elution time: 0-4.0 min, eluent as follows:
Figure BDA0002321528230003491
Figure BDA0002321528230003501
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in table 3:
TABLE 3
Figure BDA0002321528230003502
Figure BDA0002321528230003511
Figure BDA0002321528230003521
NA indicates no detection or no detection (limit of detection of blood concentration is 1ng/ml, C is detected in blood max When the NA is NA, the NA in the blood detection index is not detected; when blood is detected C max When the content is higher than the limit of quantitation by 1ng/ml, the NA in the blood detection index is not detected; NA in tissues (colon and ileum) indicates not detected).
And (4) experimental conclusion:
as can be seen from the results of the mouse Pharmacokinetic (PK) experiments in the table: the compounds of the examples of the invention showed good exposure levels in the colon and ileum, area under the time curve of plasma drug concentration (AUC) and maximum plasma drug concentration (C) max ) All reach the screening standard; and the colon/ileum drug concentration ratio and the colon/plasma drug concentration ratio of the compound are high, and good selectivity is shown.
Test 4, in vivo efficacy test procedure and results
4.1 purpose of experiment:
the compounds of the examples were evaluated for efficacy in a DSS (dextran sulfate sodium) induced C57BL/6 mouse colitis model.
4.2. Experiment main material
4.2.1 instruments
1. Balance Mettler toledo AL104
2. Balance TP-602
4.2.2 reagents
1. Dextran Sodium Sulfate (DSS): MP Biomedicals, LLC, solon, ohio, cat No.: 160110
2. Cyclosporine (CsA): norwalk, switzerland, batch number: S0033A
3. Sodium carboxymethylcellulose: chemical reagents of national drug group Limited
4. Tween 80: sigma, cat # s: 8CBM 513V
4.2.3 Experimental animals
Animal species and strains: C57BL/6
sex, age/body weight: female, 6-8 weeks old/18-20 g
The supplier: Shanghai Slac Experimental Animal Co.,Ltd.
4.3. experimental procedure
4.3.1 grouping
Animals were randomized into groups based on animal weight on day-1 using BioBook software to ensure similar weight values for each group of animals to reduce bias, and the grouping and dosing schedule are shown in the table below.
Grouping and dosing regimens
Figure BDA0002321528230003531
Figure BDA0002321528230003541
a solvent 0.5% CMC-Na +1%
b, at intervals of 8 hours
4.3.2 Experimental procedures
1. Reagent preparation
DSS-containing drinking water: dissolving an appropriate amount of DSS powder in autoclaved drinking water, to prepare 2% DSS solution.
2. Induction of enteritis
On day-1, animals were divided into 12 groups of 10 animals on average. (specific grouping scheme see Table 1)
Starting on day 0, 9. The day of molding was counted as 0 day. The DSS aqueous solution is wrapped by tin foil paper to ensure light resistance. The DSS aqueous solution was replaced every 2 days.
Group 1 mice were free to drink normal water for 9 days (from day 0, 9, 00 to day 9 before necropsy).
3. Administration of drugs
The specific dosages, routes of administration and times of administration are referenced in the table above.
4.4 measurement
1) Body weight
The frequency of recording was once a day.
2) Daily disease index (DAI)
The frequency of recording was once a day, rated on 4 scales according to the following criteria:
weight change (0, less than or equal to 1%;1,1-5%;2,5-10%;3, 10-15%;4, > 15%);
bloody stools (0, negative; 4, positive);
Stool score (0, normal; 2, loose stool; 4, diarrhea)
The daily disease index value (DAI) was obtained by dividing the sum of the scores of the above 3 sections by 3. The DAI-time (day) curve was plotted against the daily DAI score and the peak area under the curve (AUC) was calculated. The DAI AUC reduction ratio is calculated by comparing the administration group with the Vehicle group, and the calculation formula is (DAI AUC) Administration set -DAI AUC Vehicle )/DAI AUC Vehicle ×100％
4.5. The experimental results are as follows:
Figure BDA0002321528230003542
Figure BDA0002321528230003551
4.6. conclusion of the experiment
On a DSS-induced C57BL/6 mouse colitis model, the compounds of the above examples can significantly reduce the daily disease index (DAI) and have obvious drug effects.

Claims (11)

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I-3):
Figure FDA0003872174020000011
wherein the content of the first and second substances,
L 1 is-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -；-C(O)-、-C(O)CH 2 -、-CH 2 C(O)-；-C(O)CH 2 NH-、-C(O)CH 2 N(CH 3 )-、-C(O)CH 2 NHCH 2 -、-C(O)CH 2 NH(CH 2 ) 2 -、-CH 2 C(O)N(CH 3 )-；-S(O) 2 -；
L 2 Is an oxygen atom, or-NR 4 -；
R 4 Selected from a hydrogen atom, or C 1 -C 3 Alkyl groups of (a);
L 3 is-NH-;
ring B is selected from
Figure FDA0003872174020000012
Ring C is a 5-6 membered monoheteroaryl group with "heteroatom selected from N, heteroatom number 1-3";
R 1 is a hydrogen atom, C 1 -C 3 Alkyl, cyano, 4-6 membered heteromonocyclic group with 1-3 heteroatoms selected from one or more of N and O, phenyl, or 5-6 membered heteroaryl with 1-3 heteroatoms selected from N; said mono-or heteroaryl being optionally further substituted by C 1 -C 3 Alkyl, or cyano of (a);
R 2 selected from hydrogen atom, C 1 -C 3 Alkyl group of (A) or (B),
Figure FDA0003872174020000013
Said alkyl group being optionally substituted by C 1 -C 3 Alkoxy or heterocyclyl, the heterocyclyl being selected from
Figure FDA0003872174020000014
Said heterocyclyl being optionally substituted by C 1 -C 6 Alkyl substitution;
R 3 selected from hydrogen atom, C 1 -C 3 Alkyl of (2), or C 1 -C 3 Hydroxyalkyl of (b);
x is 0, 1 or 2;
y is 0, 1, 2 or 3.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 4 Is methyl, ethyl, propyl or isopropyl.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, wherein R is 4 Selected from methyl.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein ring C is selected from the group consisting of
Figure FDA0003872174020000021
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 The 4-to 6-membered heteromonocyclic group in (1) is selected from:
Figure FDA0003872174020000022
Figure FDA0003872174020000023
6. the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 The 5-6 membered heteroaryl group in (1) is selected from:
Figure FDA0003872174020000024
Figure FDA0003872174020000025
7. the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the compound of formula (I) is selected from the group consisting of:
Figure FDA0003872174020000026
Figure FDA0003872174020000031
Figure FDA0003872174020000041
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
9. Use of a compound of general formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 in the preparation of a JAK inhibitor medicament.
10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of inflammatory diseases selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease and neoplastic diseases selected from myelofibrosis, polycythemia vera and essential thrombocythemia, acute myeloid leukemia, acute lymphocytic leukemia, ductal breast cancer and non-small cell lung cancer and wherein the inflammatory bowel disease is a chronic inflammatory disease of the intestinal tract.
11. The use according to claim 10, wherein the chronic inflammatory bowel disease is selected from ulcerative colitis and Crohn's disease.
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